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Unveiling the Cuproptosis in Colitis and Colitis-Related Carcinogenesis: A Multifaceted Player and Immune Moderator
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Jingwen Liu1, †, Hairuo Huang2, †, Xiaojie Zhang3, †, Yang Shen4, DeMing Jiang5, Shurong Hu1, Shuyan Li6, Zelin Yan7, Wen Hu7, Jinhua Luo3, Haibo Yao8, *, Yan Chen1, *, Bufu Tang9, *
Research. Vol 8 Article ID 0698
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Research. Vol 8 Article ID 0698
• Review Article •
Unveiling the Cuproptosis in Colitis and Colitis-Related Carcinogenesis: A Multifaceted Player and Immune Moderator
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Jingwen Liu1, †, Hairuo Huang2, †, Xiaojie Zhang3, †, Yang Shen4, DeMing Jiang5, Shurong Hu1, Shuyan Li6, Zelin Yan7, Wen Hu7, Jinhua Luo3, Haibo Yao8, *, Yan Chen1, *, Bufu Tang9, *
Affiliations
  • 1 Department of Gastroenterology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 2 China Medical University, Shenyang 110122, China.
  • 3 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
  • 4 Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200000, China.
  • 5 Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou 310007, China.
  • 6 Department of Nursing, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 7 Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China.
  • 8 Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou 310014, China.
  • 9 Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200000, China.
Published: 2025-05-14 doi: 10.34133/research.0698
Outline
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Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.

Jingwen Liu, Hairuo Huang, Xiaojie Zhang, Yang Shen, DeMing Jiang, Shurong Hu, Shuyan Li, Zelin Yan, Wen Hu, Jinhua Luo, Haibo Yao, Yan Chen, Bufu Tang. Unveiling the Cuproptosis in Colitis and Colitis-Related Carcinogenesis: A Multifaceted Player and Immune Moderator[J]. Research, 2025 , 8 (5) : 0698 . DOI: 10.34133/research.0698
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Introduction
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Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are worldwide health concerns, characterized by increasing prevalence and death rates. making them major threats to human health [1,2]. In defending against pathological cells, both involve various cells from innate and adaptive immunity [3]. IBD is fundamentally mediated by immune surveillance mechanisms that detect commensal microbiota and counteract proinflammatory mediators through coordinated mucosal barrier defenses, whereas CRC predominantly engages T cell-mediated immunosurveillance to detect and neutralize aberrant neoplastic cell proliferation through tumor-associated antigen recognition systems [4,5]. IBD represents a collection of persistent and recurrent inflammatory disorders that target the gastrointestinal system. Despite extensive research, the underlying mechanisms driving its development remain largely elusive [6,7]. It is widely accepted that the pathogenesis of the disease arises from a multifaceted interaction among genetic predisposition, environmental triggers, microbial influences, and immune system dysregulation. While these elements are crucial to disease development, none of them alone is adequate to initiate the disease, with the immune microenvironment serving as a key contributor [8,9]. On the other hand, CRC stands as a prevalent form of cancer affecting the digestive system. Early diagnosis and treatment remain challenging, and the prognosis is poor, with increasing incidence and mortality rates. CRC accounts for approximately 10% of global cancer incidence and mortality, ranking as the second most prevalent etiology of cancer-related deaths worldwide [10]. Its pathogenesis is similar to that of most cancers, starting with abnormal crypts and gradually progressing to precancerous lesions (polyps), eventually developing into malignant tumors over 10 to 15 years. Current therapeutic strategies encompass endoscopic or surgical resection for localized lesions, neoadjuvant radiotherapy to achieve tumor downstaging, and systemic therapeutic regimens incorporating molecular-targeted agents and immune checkpoint inhibitors, reflecting contemporary advances in precision medicine [11]. Chronic inflammation has long been associated with the development of cancer. Patients with IBD are at a higher risk of developing CRC, which represents a severe complication of chronic inflammation. This risk correlates with disease duration, extent of inflammation, and cumulative inflammatory burden [12]. Therefore, elucidating the pathogenesis of IBD and the molecular mechanisms underlying inflammatory microenvironment alterations is crucial for both IBD treatment and the prevention of IBD-associated CRC. With societal development, changes in lifestyle and dietary habits have correspondingly increased the rate of IBD and CRC. The occurrence of IBD ranges from 7% to 14%, while CRC incidence is approximately 10%, posing marked health risks to individuals, families, and society [10,13]. This urgent public health issue necessitates the advancement of innovative diagnostic approaches and treatment modalities, including targeted drugs.
Copper (Cu) plays an indispensable role in maintaining essential biological processes and physiological homeostasis, while its homeostatic imbalance can lead to cell apoptosis and various diseases. For instance, excessive Cu levels result in Wilson's disease [14], whereas Cu deficiency causes Menkes disease [15]. We have systematically categorized the differential effects of varying copper levels in vivo to elucidate how specific concentration thresholds may trigger tumorigenic responses (Table 1).
Research on cell death induced by Cu has been conducted for many years, and it was only in 2022 that Tsvetkov uncovered a novel type of regulated cell death resulting from Cu, termed “cuproptosis” [16]. Excess intracellular Cu targets lipoacylated proteins within the tricarboxylic acid (TCA) cycle, leading to their accumulation and triggering cell death. This discovery has opened new therapeutic avenues for treating IBD and CRC [17]. Cuproptosis exerts complex bidirectional regulatory effects on IBD and CRC. On the one hand, excessive Cu promotes inflammation and tumor progression through mechanisms such as enhanced cell proliferation, induction of drug resistance, stimulation of angiogenesis and metastasis, and increased reactive oxygen species (ROS) production [18–20]. On the other hand, disease suppression can also be accomplished through the use of copper chelators, which suppress angiogenesis while controlling cancer progression and metastasis, targeting cuproptosis to promote tumor cell death, and utilizing copper ion carriers for immunoregulation [21–23]. This review systematically delineates the ambivalent regulatory mechanisms of copper homeostasis and cuproptosis in the pathophysiology of IBD and CRC, while elucidating the therapeutic efficacy of copper-modulating agents through comprehensive analysis of their molecular targets and clinical translational potential. Additionally, we elucidate the impact of the immune microenvironment on cuproptosis and highlight the possibility of modulating cuproptosis as a therapeutic approach to overcome resistance to chemotherapy and immunotherapy, providing new insights for the advancement of next-generation pharmacological agents that induce cuproptosis. Finally, we discuss the latest progress in potential molecular targets of cuproptosis and associated genes in managing IBD and CRC, highlighting the key areas of future research and the pressing issues that need to be addressed.
Cu Metabolism and Cuproptosis
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Cu metabolism
Cu constitutes an indispensable trace element crucial for maintaining optimal physiological functions in humans, participating in various signaling pathways and closely associated with inflammatory factors and tumor-related molecules [24]. The principal dietary sources of Cu comprise organ meats, meat, and shellfish, with a recommended daily intake of 0.8 to 2.4 mg to maintain systemic Cu homeostasis [25]. Dietary Cu absorption mainly takes place in the initial segment of the small bowel and its adjoining regions and depends on Cu transport protein 1 (CTR1), also referred to as solute carrier family 31 member 1 (SLC31A1), and excessive absorption of Cu ions via CTR1 can lead to cuproptosis. Once absorbed, Cu is transferred into circulation through ATPase copper transporting alpha (ATP7A) and transported to the hepatic region via the portal circulation, where it is primarily stored. Within hepatocytes, Cu is predominantly sequestered by metallothionein 1 and 2 for storage [26–28]. Subsequently, Cu is released back into the bloodstream through ATPase copper transporting beta (ATP7B). In this phase, it binds once again to soluble chaperone proteins, which play a crucial role in safely transporting copper to various specific tissues and organs where it is needed for essential biological functions [29]. In target tissues, Cu modulates diverse physiological processes, encompassing immune regulation, redox homeostasis maintenance, and intestinal microbiota modulation. Excess Cu is excreted via feces after binding to amino acids in bile, with a small portion excreted through the intestinal epithelium [30] (Fig. 1).
Cuproptosis
First proposed by Tsvetkov and colleagues in 2022, the term “cuproptosis” describes a newly identified pathway through which copper triggers cellular demise (Fig. 2). This process distinguishes itself from established cell death modalities, including apoptosis and necrosis, but more closely resembles ferroptosis. Tsvetkov et al. demonstrated that copper ionophore-induced cell death occurs independently of classical apoptotic markers, as evidenced by the absence of caspase-3 cleavage or activation. Notably, genetic ablation of key apoptotic effectors BAX and BAK1, or pharmacological inhibition of caspases using pan-caspase inhibitors, failed to prevent copper ionophore-mediated cell death, clearly distinguishing this process from apoptosis. Furthermore, neither necroptosis inhibitors nor ferroptosis inhibitors could attenuate copper-induced cell death [16]. Cuproptosis, on the other hand, is characterized by a unique mechanism and cannot be reversed or rescued using traditional cell death inhibitors (e.g., apoptosis inhibitors or ferroptosis inhibitors). Consequently, the application of copper chelators can effectively remove excess copper ions, thereby preventing copper-induced cellular damage and rescuing the cells [16].
Research has demonstrated that Cu ionophores, like disulfiram (DSF) [31] and elesclomol (ES) [32], promote Cu overload within cells, particularly in mitochondria [33]. Excessive copper levels directly interact with lipoacylated elements in the TCA cycle, triggering the buildup of lipoacylated proteins and the reduction of Fe-S cluster proteins, and protein misfolding. This results in mitochondrial dysfunction, such as disrupted oxidative phosphorylation and the excessive accumulation of ROS [16]. The specific mechanism involves the reduction of Cu2+ to Cu+ by ferredoxin 1 (FDX1) in mitochondria. FDX1 is recognized as a key upstream regulator of the lipoic acid (LA) pathway. Governed by FDX1, lipoic acid synthetase (LIAS) facilitates the attachment of LA moieties to dihydrolipoamide S-acetyltransferase (DLAT). Cu ions form direct coordination bonds with the LA moiety of lipoacylated DLAT through disulfide linkages, inducing DLAT oligomerization and subsequent proteotoxic stress [16]. As mitochondrial dysfunction progresses and ROS levels rise, intracellular stress response pathways are activated, inducing cell death via multiple pathways characteristic of cuproptosis [34] (Fig. 3). Given that the intestine serves as the main site for copper absorption, dysregulated Cu metabolism may induce cuproptosis in intestinal epithelial or immune cells, further exacerbating the loss of intestinal barrier function. This process may exacerbate intestinal inflammation and promote tumorigenesis, thereby establishing a mechanistic link between Cu-induced cytotoxicity and the pathogenesis of both inflammatory disorders and malignant transformations in the gastrointestinal tract.
The mechanisms of cuproptosis hold promising potential for clinical treatment across various diseases. The molecular components implicated in this process may be exploited to trigger cuproptosis in pathological cells, offering innovative therapeutic avenues for drug development (Table 2) [16,17,35–47]. In the course of cuproptosis induction, FDX1 serves as a key upstream regulator of the LA pathway, serving a pivotal role in controlling protein lipoylation. In CRC, reduced FDX1 expression is frequently linked to advanced stages of cancer and metastatic features, resulting in shorter overall survival [48,49]. Moreover, the dysregulation of Cu transport proteins, including ATP7A, ATP7B, and SLC31A1, can disrupt cellular function [24]. SLC31A1 regulates copper uptake into cells, whereas ATP7A and ATP7B regulate copper efflux, all of which is essential in Cu transport and homeostasis [50–52]. However, further investigation is required to elucidate the precise molecular mechanisms governing these transporters' function, their associated genetic regulators, and their role in cuproptosis induction. This will be essential for translating the molecular mechanisms of cuproptosis into actionable therapeutic strategies for CRC and other diseases.
Interaction between Cuproptosis and the Intestinal Immune Microenvironment
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Immune microenvironment
The tumor microenvironment (TME) is characterized as the local cellular environment surrounding tumors or cancer stem cells [53]. The neoplastic milieu consists of various immunocytes, lymphocytes, extracellular matrix (ECM), vascular networks, and inflammatory cell populations [54]. The immune microenvironment, as the core component of the TME, plays an essential role in maintaining body health, participating in immune responses, and influencing tumor progression. Current evidence demonstrates that both immune cell populations and stromal components play critical roles in the activation and aggregation processes, and reprogramming of the extracellular matrix, and these changes result directly from the intricate crosstalk between tumor cells and the TME [55]. Evaluation of the immune microenvironment provides significant prognostic value and represents a robust adjunct to conventional histopathological and molecular biomarker analysis. This integrated evaluation approach allows for more accurate predictions of patient responses to immunotherapy, providing more comprehensive evidence for personalized treatment strategies [56] (Table 3).
In recent years, Cu, as an essential element for the function of various immune cells, has been found to influence the balance of the immune system. Both excess and deficiency of Cu can disrupt immune homeostasis, promoting an immunocompromised state. For instance, cytokines in the immune microenvironment (e.g., tumor necrosis factor-α [TNF-α] and interleukin-10 [IL-10]) regulate the expression of Cu transport proteins, thereby affecting Cu uptake, excretion, and distribution within the body, ultimately altering Cu metabolism [34]. Understanding the interactions between Cu metabolism, cuproptosis, and the immune microenvironment not only sheds light on their roles in disease pathogenesis but also provides new research directions and treatment approaches for disease treatment.
Induction of immune antitumor effects by cuproptosis
Immunogenic cell death (ICD) represents a unique type of controlled cell demise that has the capacity to elicit an adaptive immune response. A hallmark of ICD involves the secretion of DAMPs (damage-associated molecular patterns) [57]. DAMPs can be divided into 5 categories: nucleic acids, proteins, ions, glycans, and metabolites. These molecules facilitate antigen recognition and phagocytosis by binding to antigen-presenting cells, thereby enhancing apoptotic cell clearance. These antigens are then processed and displayed to T lymphocytes, initiating specific immune reactions [58]. Additionally, activation of DAMP-sensing receptors induces the secretion of inflammatory cytokines, promoting the attraction of immune cells and triggering inflammatory responses [59].
Studies have demonstrated that Cu complex nanoparticles (Cu(I)NPs) capable of inducing cuproptosis can trigger ICD and activate adaptive immune responses. This process potently augments antitumor immunity and remodels the tumor immune microenvironment [58] (Fig. 4). Thus, specific activation of cuproptosis may help reactivate the TME and facilitate the eradication of cancer cells [60]. Currently, the immune regulatory molecules CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1 (programmed cell death protein 1) have been the focus of extensive investigation [61]. However, the efficacy of immune checkpoint inhibitors is often limited by the immunosuppressive TME. To overcome this obstacle, researchers have developed a novel therapeutic strategy based on cuproptosis. The copper ionophore celastrol not only effectively delivers copper ions but also depletes overexpressed glutathione (GSH) in cancer cells, thereby inducing a self-amplifying cuproptosis process within tumor cells. The celastrol–copper (Cel–Cu) coordination NPs formed by Cel and copper ions not only efficiently trigger cuproptosis but also induce ICD, promoting the reprogramming and maturation of the immune microenvironment. This combination strategy significantly suppresses tumor progression through the synergistic effects of cuproptosis and ICD, effectively overcoming drug resistance caused by the immunosuppressive microenvironment. Notably, the Cel–Cu NPs exhibit excellent tumor-targeted accumulation and favorable biosafety [62]. In addition, cuproptosis results in the exocytosis of antigens associated with tumors, which are detectable by the body's defense mechanisms, thereby triggering the activation of immune responses. This mechanism potentiates antitumor immunity and synergizes with established immunotherapeutic regimens, augmenting their clinical efficacy. Therefore, cuproptosis activators could serve as a complementary strategy to existing immunotherapeutic drugs, providing stronger antitumor responses for cancer treatment [63].
Role of cuproptosis in intestinal immunity
The intestinal barrier serves as the primary defense against pathogenic microbial invasion [64]. Its dysfunction is implicated in various diseases, including IBD, acute pancreatitis, and CRC [65–67]. Intestinal barrier homeostasis is co-regulated by commensal microbiota and the immune system. When a small number of commensal bacteria penetrate the mucus layer, they are captured by intestinal DCs and presented to T and B cells. This process stimulates B cells to produce bacteria-specific IgA antibodies. Concurrently, macrophages in the lamina propria are activated to perform phagocytic and secretory functions. Antimicrobial peptides (e.g., defensins) are secreted to eliminate commensal bacteria that approach epithelial cells [68,69]. Another mechanism maintaining intestinal homeostasis involves the aryl hydrocarbon receptor (AHR) pathway. AHR activation triggers IL-22 release, up-regulates IL-10 receptor expression, and enhances tight junction formation between intestinal epithelial cells, thereby reinforcing barrier integrity [70].
The intestinal immune response involves various cells from both innate and adaptive immunity, with STING (stimulator of interferon genes) pathway via cGAS (cyclic GMP-AMP synthase) emerging as a key innate immune signaling pathway [3,71,72]. Research has shown that cuproptosis can enhance cancer immunity through the cGAS-STING signaling pathway [73,74]. Tumor antigens released during cancer cell death are absorbed by dendritic cells (DCs) [75]. In DCs, cyclic GMP-AMP (cGAMP) activity is heightened, inducing a robust inflammatory response characterized by increased IL-2, TNF-α, and CXCL10/11 secretion, which collectively induce inflammation [74]. Additionally, Cu oxide NPs dissolve in macrophage lysosomes, inducing cuproptosis defined by mitochondrial dilation and indicators of oxidative stress [76]. DSF/Cu enhances M1 macrophage polarization while modulating glucose metabolic reprogramming via the mTOR (mechanistic target of rapamycin) pathway [77]. Moreover, the combination of DSF/Cu and CD47 inhibition demonstrates a synergistic therapeutic impact, facilitating DC maturation and significantly enhancing the cytotoxic function of CD8+ T cells, thus boosting the antitumor immune response [78]. Inducing cuproptosis in localized tumors significantly impacts the immune microenvironment, influencing tumor-infiltrating immune cells and improving immunotherapy outcomes. For example, IL-10, an anti-inflammatory cytokine secreted by intestinal DCs, functions to suppress inflammatory responses. Overactive inflammatory responses in macrophages during IBD may also serve as effective intervention points [79,80]. By leveraging the regulatory mechanisms of cuproptosis, new therapeutic strategies can be developed to alleviate intestinal diseases and modulate immune responses.
Bidirectional Regulation of Cu in IBD
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Cu plays a complex bidirectional role in IBD. Its metabolic balance and cuproptosis mechanisms function differently under varying pathological conditions. On one hand, as a crucial cofactor for key antioxidant enzymes, Cu effectively scavenges ROS and precisely modulates immune responses, thus maintaining gut barrier stability and reducing inflammatory responses [81]. On the other hand, Cu imbalance or overabundant accumulation can exacerbate oxidative stress, induce apoptosis or necrosis in intestinal epithelial cells, and weaken tight junction proteins, thereby promoting IBD progression [82]. Understanding the bidirectional regulation of Cu metabolism and cuproptosis in IBD offers valuable insights into its pathogenesis and provides theoretical grounds for developing targeted therapeutic strategies.
Proinflammatory effects of Cu
Oxidative stress
ROS naturally arise as metabolic by-products during normal cellular physiological processes [83]. Within the inflammatory intestinal mucosal environment, the release of ROS and other inflammatory markers directly damages intestinal epithelial cells and disrupts the delicate pathways of proinflammatory reactive substances in immune cells [84]. Elevated ROS levels, combined with diminished antioxidant capacity, represent key pathogenic factors in IBD development [85].
Evidence increasingly suggests a close association between disrupted intracellular Cu metabolism and oxidative stress [86,87]. Excess copper, as a potent oxidant, induces ROS generation and elicits inflammatory responses. Studies have found that Cu ion carriers can induce ROS generation and activation of pro-apoptotic signaling pathways, containing the JNK (c-Jun N-terminal kinase) pathway and the MAPK (mitogen-activated protein kinase) pathway, and inhibit anti-apoptotic nuclear factor kappa B (NF-κB) signaling [88,89]. Additionally, cuproptosis specifically targets lipoacylated components associated with the TCA, resulting in the destabilization of Fe-S cluster proteins and consequent disruption of mitochondrial respiratory chain activity, which has been linked to IBD [90]. Impaired mitochondrial function induces a state of bioenergetic crisis, weakening epithelial barrier integrity by heightening prone to cuproptosis and decreasing the production of secretory barrier components, and impairing regeneration in response to damage [91–93]. To effectively manage IBD onset and progression, oxidative stress must be mitigated via antioxidant or anti-inflammatory strategies, such as Cu chelators [94], cuproptosis-related proteins like GSH [83], phenolic and polyphenolic compounds [95], and hormonal therapies [96,97].
Intestinal immune dysbiosis
Chronic intestinal inflammation involves dysbiosis of gut microbiota, compromised epithelial barriers, immune cell activation, and reduced immune tolerance to bacteria [98–100]. Under normal conditions, the gut microbiota and host immune system maintain a dynamic equilibrium to protect against pathogens and preserve intestinal homeostasis [101]. When small amounts of commensal bacteria penetrate the mucus layer, immune cells within the mucosal layer become activated to eliminate bacteria nearing epithelial cells by producing antimicrobial substances like defensins [69]. Activated macrophages are marked by increased mitochondrial Cu2+ levels, which catalyze NADH redox cycling and promote metabolic changes, triggering epigenetic modifications associated with inflammation [102]. Targeting mitochondrial Cu (Cu2+) has been shown to restore gut homeostasis by inhibiting the production of key metabolites necessary for initiating and sustaining inflammation [102]. Excessive copper intake induces oxidative damage, initiating cuproptosis in intestinal epithelial cells. This cascade disrupts gut barrier integrity, alters microbiota equilibrium, and establishes a proinflammatory feedback cycle [103–105]. Therefore, Cu ion levels are essential for immune cell metabolism and gut microbiota equilibrium, positioning Cu serving as a possible target for controlling uncontrolled inflammation [106].
Anti-inflammatory effects of Cu
Regulation of the NF-κB pathway by COMMD1
The pathogenesis, progression, and treatment of IBD are complex processes, with Cu-related enzymes and proteins playing key roles. Critical examples include COMMD1 (copper metabolism MURR1 domain-containing protein 1), IκB (an NF-κB family member), and cytochrome c oxidase 17 (COX17). Strong evidence links NF-κB to the development of IBD. Within the inflamed intestinal mucosa of IBD patients, dysregulated expression of NF-κB precursors, NF-κB itself, and immune receptors stimulated by NF-κB (such as NOD2 [nucleotide-binding oligomerization domain-containing protein 2]) has been observed. Additionally, the regulation of downstream genes associated with NF-κB, such as interleukins IL-12 and IL-23, is also disrupted [107]. Persistent NF-κB activation drives mucosal inflammation and epithelial barrier disruption through up-regulation of proinflammatory cytokines and induction of intestinal epithelial cell apoptosis [108]. COMMD1 is a multifunctional protein involved in Cu excretion regulation in the liver, sodium uptake via epithelial sodium channels (ENaC), and NF-κB signaling modulation [109]. Growing evidence indicates that COMMD1 engages with the ubiquitin–proteasome pathway, influencing the degradation of NF-κB elements, ATP7B, and hypoxia-inducible factor-1α (HIF-1α) [110,111].
Within the NF-κB signaling cascade, PAMPs (pathogen-associated molecular patterns)/DAMPs and inflammatory signaling molecules (e.g., TNF-α and IL-1) activate membrane receptors, leading to IκB phosphorylation by IκB kinase (IKK) and ensuing breakdown by the proteasome. This releases the RelA/p50 heterodimer, which translocates to the nucleus to modulate gene transcription [107]. COMMD1 interacts with the ECS–SOCS1 complex (composed of Elongins B/C, SOCS1, and Cullin2), promoting NF-κB ubiquitination and RelA degradation, thereby inhibiting NF-κB-mediated transcription [112] (Fig. 5). As a regulator of copper transport pathways, COMMD1 specifically interacts with NF-κB subunits to inhibit their transcriptional activity [113,114]. Notably, COMMD1 occupancy at promoter sites persists even after RelA removal, suggesting that COMMD1 inhibits NF-κB target gene expression through this mechanism [115]. Overexpression of COMMD1 reduces RelA chromosomal binding time and IκB ubiquitination, thereby suppressing IBD onset [116,117].
Reduced COMMD1 expression in circulating leukocytes of IBD patients leads to heightened NF-κB transcriptional activity, while COMMD1 deficiency in myeloid cells exacerbates inflammatory responses. Murine models reveal that myeloid-specific COMMD1 deficiency exacerbates LPS-induced IBD manifestations [118]. This highlights the anti-inflammatory role of COMMD1, with its deficiency potentially increasing the risk of colitis-associated cancer. Cu-related drugs and proteins, such as tetrathiomolybdate (TTM; a potential NF-κB transcription inhibitor), transgenic overexpression of Cu/ZnSOD (shown to alleviate DSS-induced colitis), and GPx1/GPx2 (or GSH biosynthesis inhibitors like buthionine sulfoximine), hold promise as therapeutic options for reducing inflammation and treating IBD [107,119,120].
Modulating the function of HIF-1α
Inflammation represents a fundamental pathological characteristic of IBD, and hypoxia is considered a normal phenomenon in most inflammatory processes. HIF-1α functions as a central regulator that facilitates intestinal cellular adaptation to hypoxia and preserves intestinal homeostasis [121]. HIF-1α exerts broad physiological effects, triggering transcription by binding to hypoxia response elements (HREs) in various genes [122]. This regulation of cellular hypoxic responses is essential for both physiological adaptation to low oxygen and inflammatory modulation [123,124]. Since HIF-1α enhances intestinal epithelial barrier function, it is a potential therapeutic target for addressing epithelial barrier dysfunction in IBD.
Research has demonstrated that Cu can enhance HIF-1α stability and facilitate its accumulation [125]. Moreover, copper potentiates HIF-1α accumulation and modulates its transcriptional activity by altering HRE binding in target genes [126–128]. The underlying mechanism suggests that copper, by facilitating the transport of the CCS (copper chaperone for superoxide dismutase 1 [SOD1]), ensures that HIF-1α can selectively bind to its target genes (e.g., BNIP3). Furthermore, the interaction dynamics between HIF-1α and the HREs within its gene targets is copper-dependent, given copper's essential function in assembling the HIF-1 transcriptional machinery, and it amplifies the production of factors such as VEGF (vascular endothelial growth factor). In addition, elevated copper levels can stabilize HIF-1α, causing its cytoplasmic buildup and subsequent activation of the HIF-1 signaling cascade [129] (Fig. 6). Additionally, Cu participates in modulating the assembly of the HIF-1α transcriptional complex. In this context, Cu may inhibit HIF-1α activity to maintain the ability of HIF-1α to bind its cofactors. While Cu deprivation does not impact the expression of HIF-1α, excessive Cu can enhance the functionality of HIF-1α through mechanisms shared by other nonessential transition metals [126]. This enhancement enables cells to adapt to hypoxic and inflammatory environments, thereby influencing the onset, progression, and treatment of IBD.
Bidirectional Regulation of Cu in CRC
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Cu acts as a vital micronutrient, contributing significantly to core biological activities and systemic functions, particularly in enzymatic reactions, redox processes, and energy metabolism [130]. Cu homeostasis is crucial for maintaining proper cellular function [131]. Since the discovery of cuproptosis, researchers have reexamined the involvement of Cu and Cu-triggered cellular demise in tumorigenesis, bringing Cu back into focus in cancer research. CRC, a malignancy with high incidence and mortality rates, involves complex pathological mechanisms, with dysregulated copper metabolism and cuproptosis emerging as critical areas of investigation. Research has demonstrated that aberrant Cu accumulation can drive CRC progression by triggering oxidative stress, disrupting DNA repair mechanisms, and stimulating cellular proliferation and metastatic activity. At the same time, Cu-mediated cell death mechanisms, such as inducing mitochondrial damage and intrinsic apoptosis, may exert inhibitory effects on tumor growth [34]. Collectively, the biphasic regulation of Cu homeostasis in CRC underscores its therapeutic potential as a druggable target. Elucidating this mechanism holds great importance for understanding the molecular pathology of CRC and designing targeted therapeutic approaches (Fig. 7).
Pro-tumor effects of Cu
Tumor angiogenesis
Angiogenesis refers to the creation of neovascularization from established vasculature, supplying oxygen and vital nutrients to rapidly dividing tumor cells [132,133]. This process comprises multiple coordinated steps, including endothelial cell proliferation and migration, vascular basement membrane remodeling, and de novo vascular network formation [132]. McAuslan was the first to suggest the angiogenic-promoting characteristics of copper, noting that copper salts could stimulate the movement of vascular lining cells, which is a vital initial phase in the process of angiogenesis. Subsequent studies demonstrated that topical copper application induces neovascularization in the rabbit corneal model. Furthermore, research has shown that copper substantially enhances the growth and activity of vascular endothelial cells [134].
When tumor development exceeds the supply of existing blood vessels, the tumor tissue enters a hypoxic state. Under these conditions, intracellular copper stabilizes HIF-1α, thereby promoting angiogenesis. Excess Cu increases the NF-κB's transcriptional activity, boosting the production of pro-angiogenic factors, thereby promoting blood vessel formation [135,136]. Cu homeostasis is regulated by proteins such as ATP7A, a Cu-exporting protein that maintains intracellular Cu levels to safeguard cells against copper toxicity. ATP7A expression is posttranscriptionally regulated by copper levels and facilitates copper delivery to oncogenesis-associated cuproenzymes, including those driving cell proliferation, metastasis, and angiogenesis [137]. Additionally, SOD1, a modulator of vascular constriction, can boost VEGF production and potentiate FGF (fibroblast growth factor)-driven angiogenesis, facilitating the formation of tumor-associated vasculature [34]. Likewise, antioxidant 1 (ATOX1), a copper chaperone, has emerged as a pivotal regulator in the angiogenic process. Silencing ATOX1 inhibits stimulation of migration in smooth muscle cells of blood vessels through the action of PDGF, suggesting its crucial role in tumor angiogenesis [138]. In summary, Cu's ability to modulate multiple angiogenic factors highlights its potential to promote tumor progression by supporting new blood vessel formation essential for tumor growth.
Cu-dependent proteins driving cancer metastasis
Cu constitutes a fundamental element in numerous enzymes and proteins that are intricately involved in cancer biology, such as SOD1, lysyl oxidase (LOX), and CCS [139]. These Cu-dependent proteins promote cancer metastasis through activation of oncogenic enzymatic pathways. The copper chaperone CCS mediates the delivery of Cu ions to SOD1. SOD1 is essential for preserving intracellular redox balance. Upon binding zinc and copper ions, this enzyme demonstrates robust catalytic activity that facilitates superoxide anion radical dismutation, thereby reducing intracellular oxidative damage. Research shows that the regulation of Cu chaperones ATOX1 and CCS is elevated in CRC, uterine cancer, and liver cancer, leading to increased activity of Cu-dependent enzymes and promoting tumor cell proliferation and metastasis [140]. Additionally, LOX, an extracellular copper-dependent enzyme, is essential for mediating the covalent crosslinking of ECM components. LOX is acknowledged as a pro-metastatic factor in CRC, prostate cancer, and liver cancer, promoting cancer cell invasion and dissemination [141].
Antitumor effects of Cu
Targeting tumor cells via cuproptosis
Disrupting the balance of ROS in cells triggers oxidative stress responses [142]. Evidence indicates that oncogenic signaling and mutations increase ROS production, which is closely associated with cancer initiation and progression. Growth factor signaling promotes ROS generation, thereby accelerating tumor progression [143–146]. ES and DSF, as copper ion carriers, selectively transport Cu to mitochondria, leading to localized ROS accumulation and inducing tumor cell death [147] (Fig. 8). The specific mechanism involves mitochondrial FDX1 reducing Cu2+ (carried by ES) to Cu+. The liberated Cu+ reacts with oxygen molecules, generating superoxide radicals, which subsequently dismutate into hydrogen peroxide. Hydrogen peroxide further reacts with Cu+ to generate highly destructive hydroxyl radicals. This cascade of reactions significantly elevates ROS levels, ultimately inducing tumor cell death [148]. Furthermore, Cu ions complexed with molecular carriers catalyze hydroxyl radical formation, amplifying oxidative stress and inducing tumor cell apoptosis. Additionally, Cu-binding proteins such as ceruloplasmin can be directed toward increase oxidative stress levels and induce tumor cell death [149]. Cuproptosis offers a tumor-suppressive mechanism, providing new opportunities for CRC treatment. It is anticipated that in the coming years, advancements in clinical diagnostics and therapeutics will further harness cuproptosis for cancer therapy.
Cu chelators regulating cancer cell immune evasion
Cancer immune evasion is widely acknowledged as one of the core characteristics of tumor progression, where tumor cells overexpress PD-L1 (programmed death-ligand 1) to escape immune surveillance. PD-L1, an immune checkpoint protein expressed on tumor cells, mediates immune evasion by suppressing antitumor immune responses [34]. Research has shown that Cu enhances PD-L1 expression in tumor cells, thus enhancing their immune escape capacity. Intracellular Cu up-regulates PD-L1 transcription and stabilizes its protein levels. Compared to normal tissues, elevated Cu levels in cancer cells significantly enhance PD-L1 expression [150].
Conversely, Cu-chelating agents reduce PD-L1 levels by diminishing tumor cell sensitivity to inflammatory signaling molecules like interferon γ (IFNγ), TNF-α, and IFNα/β. Cu deprivation down-regulates the activation through phosphorylation of STAT3 (signal transducer and activator of transcription 3), EGFR (epidermal growth factor receptor), AKT (AKT serine/threonine kinase), and GSK3β (glycogen synthase kinase 3 beta), thereby inhibiting PD-L1 transcription and modulating PD-L1 ubiquitination and stability. Cu ion carriers like DSF can increase PD-L1 stability through Cu overload [151], while Cu chelators demonstrate the potential to enhance antitumor immune responses. For instance, TTM suppresses MEK1/2 kinase activity via copper chelation, thereby inhibiting CRC progression [152]. The tumor-suppressing activity of Cu chelators has been confirmed in various cancers, like CRC and breast cancer [34]. By targeting Cu-dependent pathways involved in immune evasion, Cu chelators could provide a novel therapeutic strategy to boost antitumor immunity.
Cu metabolism and cuproptosis in the clinical application of IBD and CRC
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Inflammatory bowel disease
Currently, most IBD cases are incurable, with treatment focused on disease control and relapse prevention, often requiring surgery. Current therapeutic approaches predominantly utilize pharmacological agents including antibiotics, aminosalicylates, corticosteroids, and immunomodulators [153]. Recent progress in IBD research have highlighted the function of Cu metabolism and cuproptosis in IBD pathogenesis, offering novel therapeutic approaches.
Antioxidants
Research suggests that elevated ROS levels and reduced antioxidant defenses contribute to IBD development. Antioxidants play a critical role in IBD pathophysiology and are categorized into catalytic and noncatalytic groups based on their mechanisms of action. In the enzymatic antioxidant defense system, ATOX1 serves as a Cu chaperone and has been shown to be indispensable for maintaining intracellular Cu homeostasis, counteracting oxidative stress, and regulating gene transcription [154]. These properties establish ATOX1 as a promising therapeutic target for mitigating intestinal inflammation through dual modulation of copper homeostasis and antioxidant pathways in IBD management. Within the nonenzymatic antioxidant defense mechanisms, GSH, the most prevalent thiol in the cytoplasm, serves an essential role. GSH protects cells by scavenging free radicals and inhibiting pro-oxidants. It additionally acts as a critical component for various enzymatic reactions involved in antioxidant defense and detoxification processes, such as GPx, glutathione S-transferase (GST), and glyoxalase [83]. Studies suggest using antioxidants as an alternative therapy to anti-inflammatory drugs or immunomodulators for patients with uncomplicated gastrointestinal diseases [95]. This approach could provide more effective treatment options for IBD patients, reducing the side effects of long-term anti-inflammatory drug use and facilitating personalized treatment strategies.
Regulation of Cu proteins and pathway activities
COMMD1 is involved in various cellular mechanisms, including Cu transport, ion balance, and hypoxic responses [155]. In IBD, NF-κB dissociates from its inhibitory complex with IκB and translocates to the nucleus, where it up-regulates proinflammatory gene expression. Normally, newly synthesized IκB promotes NF-κB nuclear export to terminate the activation process. Unlike IκB, COMMD1 works in conjunction with the ubiquitin ligase Cul2, targeting nuclear-localized NF-κB for ubiquitination and subsequent proteasomal degradation, thus acting as an inhibitor of NF-κB [156]. Research indicates that inflammation suppresses COMMD1 production, creating a reinforcing feedback loop that persistently activates NF-κB, exacerbating inflammation [156]. In IBD patients, COMMD1 expression is reduced in inflamed tissues and circulating leukocytes. Colitis mouse models exhibit reduced COMMD1 expression, indicating an inflammation-mediated response that may sustain chronic inflammation [157]. Clinically, restoring or enhancing COMMD1 expression could significantly impact IBD treatment. Strategies such as inhibiting the NF-κB pathway, blocking persistent inflammatory signaling, or developing drugs targeting COMMD1 expression or function could help suppress inflammation.
Diagnosing IBD using Cu levels
IBD is prone to misdiagnosis, particularly in individuals with ileal Crohn's disease or those under 40 years of age [158]. Cu levels in the body can aid in diagnosis. Studies have found a significant correlation between the Cu-to-zinc ratio and biomarkers like C-reactive protein and calprotectin in active IBD patients. Patients with Crohn's disease demonstrate significantly higher serum copper concentrations (22.7 ± 5.49 μmol/l) compared to both ulcerative colitis patients (17.6 ± 5.15 μmol/l) and healthy controls (20.76 ± 4.06 μmol/l; P < 0.01) [159]. These results indicate that Cu levels may function as a preliminary diagnostic marker for IBD.
Colorectal cancer
Recent studies have identified a strong connection between Cu and cancer, with abnormal Cu levels emerging as a new therapeutic target. Cu concentrations in the blood of individuals with cancer are significantly higher than in healthy individuals, often exceeding 10 times the normal levels. Thus, intracellular Cu levels are closely related to tumorigenesis and progression [160].
Cu-targeted therapy for CRC
COX17 is a critical Cu chaperone in the IMS. It facilitates Cu transfer from the cytoplasm to the mitochondrial IMS, aiding in the formation of COX [161,162]. Specifically, COX17 delivers Cu to mitochondrial membrane proteins SCO1 and SCO2, facilitating its incorporation into COX2 [163]. COX17 also transports Cu to COX11 for insertion into COX1 [163,164]. Targeting COX17 emerges as a viable therapeutic strategy for eradicating both solid and hematologic malignancies [165]. In extracellular Cu transport, ATP7A and ATP7B are key Cu-exporting proteins. Under conditions of copper deficiency, ATP7A/B resides within the trans-Golgi network (TGN), enabling the movement of copper from the cellular fluid into the TGN. As Cu levels increase, ATP7A and ATP7B serve as essential proteins for copper exportation. In conditions of copper scarcity, they are localized within the TGN, aiding in the movement of Cu from the cytosol to the lumen of the TGN. After copper levels return to normal concentrations, ATP7A/B are recycled and return to the TGN. Simultaneously, under conditions of increased copper concentration, ATP7A/B undergoes from the TGN to either the cellular periphery or vesicular compartments that subsequently merge with the plasma membrane, facilitating copper efflux. Following restoration of homeostatic copper levels, ATP7A/B undergo retrograde trafficking to the TGN. Additionally, these proteins assist in transporting copper ions from the TGN to copper-laden post-Golgi vesicles. These vesicular compartments ultimately fuse with the plasma membrane through membrane fusion events, facilitating the export of copper ions to the extracellular space. This mechanism of copper excretion is evident across various cell types, including cancerous ones [34]. In hepatic cells, ATP7B specifically directs copper from secretory vesicles into bile, thereby regulating copper levels and preventing excessive accumulation. In CRC cells harboring KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations, ATP7A up-regulation inhibits Cu-induced toxicity caused by excess Cu [166]. This implies that targeting ATP7A might act as a synthetic lethal strategy to eliminate KRAS-mutant CRC cells.
Cuproptosis combined with other therapies
Targeting cuproptosis can also be combined with chemotherapy, radiotherapy, nanotechnology, photothermal therapy (PTT), and chemodynamic therapy to enhance antitumor effects [167,168]. Recent studies have established the feasibility of engineering nanodrug delivery systems for tumor-specific Cu or Cu ionophore release, inducing localized cuproptosis and enhancing treatment efficacy [169]. For example, E-C@DOX NPs contain Cu2+ and the frontline chemotherapeutic agent doxorubicin (DOX). This combination induces cuproptosis while suppressing signaling pathways linked to tumor stemness and survival, enhancing the therapeutic effect [170]. Similarly, LDH (lactate dehydrogenase)/HA (hyaluronic acid)/5-fluorouracil (5-FU) nanosheets are designed to act on malignant cells releasing Cu2+ and 5-FU, thereby effectively inducing cuproptosis and demonstrating strong tumor suppression effects [171]. Another nanoplatform, ZnPc*/Cu/SN38@NP, slowly breaks down via protonation of carboxylic acid groups or binding with Cu2+ by GSH. This process disrupts the relationships among the Cu2+-induced NPs, ultimately releasing unbound ZnPc* and SN38. Studies have shown that ZnPc* exerts a photodynamic therapy (PDT) effect, while SN38 provides chemotherapeutic activity, resulting in a synergistic dual antitumor effect [172]. Furthermore, a novel GSH-responsive nanodrug, Es@CuTCPP, was developed by loading ES onto CuTCPP nanosheets. After accumulation at the tumor site, Es@CuTCPP not only becomes highly sonosensitive upon reaction with the overexpressed GSH in the TME but also forms CuEs complexes through the co-released Cu2+ ions and chelated Es. Consequently, Es@CuTCPP enables the generation of ROS in cancer cells upon ultrasound irradiation and modulates copper metabolism, triggering substantial cuproptosis. In a CT26 colon cancer subcutaneous xenograft model, systemic administration experiments confirmed the excellent tumor-targeting capability of Es@CuTCPP, with no significant systemic toxicity or major organ damage observed. These findings robustly demonstrate that Es@CuTCPP exhibits favorable biosafety and promising potential for clinical translation [173].
PTT is a noninvasive oncological therapy in which photothermal agents absorb ambient light energy—particularly near-infrared (NIR) radiation—and transform it into heat to target and destroy tumor cells [174]. Research indicates that LPS-CuS NPs hold significant potential in immunophotothermal therapy, effectively eradicating primary CRC and completely preventing metastasis to the spleen and liver. Photothermally responsive nanoplatforms (e.g., Au@MSN-Cu/PEG/DSF) exhibit synergistic antitumor effects when combined with PTT, enabling efficient cancer cell eradication and tumor growth suppression [167]. These findings underscore the strong connection between Cu metabolism and CRC development, treatment, and prognosis. Combining cuproptosis with other therapeutic strategies to modulate Cu ion levels represents a promising approach for CRC treatment. This synergistic strategy not only enhances antitumor effects but also provides a potential avenue for improving patient outcomes.
Overcoming drug resistance with Cu-based drugs
Despite the advancement of numerous novel approaches to cancer therapy over the past few years, chemotherapy continues to be the cornerstone of cancer therapy. Platinum-based agents constitute one of the most widely employed classes of chemotherapeutics in oncology. Nevertheless, a significant obstacle in chemotherapy is the onset of therapeutic resistance, often diminishing its therapeutic impact [175,176]. Emerging evidence suggests that combining chemotherapeutic drugs with Cu ion carriers can overcome resistance. In copper ionophores and copper-based drugs, DSF and ES have received the most attention and have undergone clinical trials. In most current clinical trials involving ES and DSF, no clinical benefits were observed in unselected populations, but their safety profiles were comprehensively evaluated (Table 4).
For example, the combination of 5-FU and DSF/Cu has been demonstrated to effectively eliminate tumor cells in CRC. DSF/Cu down-regulates indicators linked to 5-FU resistance, including thymidylate synthase and CD133/CD44 [177]. Similarly, the ES–Cu complex exerts potent anticancer effects through copper-dependent mechanisms, including ROS accumulation and subsequent tumor cell death, demonstrating multimodal cytotoxic activity against malignant cells [16,178,179]. Both approaches have demonstrated significant antitumor effects in preclinical experiments; however, clinical trials have yet to yield satisfactory results [180]. One potential restrictive factor could be the challenge of maintaining persistently elevated Cu concentrations within cancer cells in clinical settings. Conducting further studies could facilitate the transition of Cu-based drugs from experimental research to clinical application, thereby providing a more effective means of overcoming tumor resistance (Table 5).
Small-molecule compounds inducing cuproptosis
Several small-molecule compounds have been identified that may increase tumor cell sensitivity to cuproptosis. Emerging studies have identified multiple bioactive compounds capable of triggering cuproptosis, a novel form of regulated cell death mediated by copper toxicity. For example, in CRC cells, 4-OI induces Cys22 alkylation of GAPDH, targeting GAPDH to suppress its activity. This inhibition disrupts glycolysis in tumor cells, promoting electrochlorination-mediated Cu precipitation. In vivo studies demonstrate that ES containing 4-OI significantly suppresses tumor growth, exhibiting potent antitumor activity. In addition, 4-OI continues to promote cuproptosis even following Nrf2 knockdown, validating its antitumor effects through GAPDH targeting [181].
Conclusion and Outlook
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Cell death is essential for preserving physiological equilibrium and maintaining tissue integrity; however, it may also represent a maladaptive reaction to harmful triggers [182]. To date, more than 10 distinct modes of cell death have been identified, including apoptosis, pyroptosis, and ferroptosis [183]. Since the identification of cuproptosis in 2022, this recently discovered cellular death pathway has garnered significant research interest due to its dual role in IBD and CRC [16]. Cu, as a vital trace element, exhibits dual roles in metabolism and is particularly critical for maintaining intestinal health [184]. On one hand, appropriate copper levels are considered to effectively suppress inflammatory responses associated with IBD. Copper can modulate inflammatory pathways such as NF-κB to inhibit excessive immune reactions and selectively eliminate transformed cells through cuproptosis. The maintenance of this homeostasis is critical for intestinal epithelial barrier function and stem cell niche balance. This protective mechanism may be related to copper's regulation of inflammatory signaling pathways or its induction of cuproptosis in tumor cells, thereby partially suppressing tumor initiation and progression. On the other hand, dysregulated copper metabolism or abnormally elevated copper levels may exacerbate IBD pathology and create favorable conditions for CRC development by promoting oxidative stress, stimulating angiogenesis, and compromising intestinal epithelial barrier integrity. This mechanism is closely linked to gut microbiota dysbiosis, as impaired barrier function further disrupts intestinal homeostasis maintained by commensal bacteria and the immune system. Studies by Roy et al. [185] have shown that IBD-associated gut microbial communities may promote disease progression through immune cell-mediated intestinal barrier damage. Thus, copper dysregulation may disrupt this delicate balance, aggravating microbial dysbiosis and immune dysfunction, ultimately forming a pathological cycle that drives IBD progression. Notably, this bidirectional regulation exhibits significant tissue specificity, with intestinal epithelial cells displaying a higher tolerance threshold for copper. Moreover, long-term low-dose exposure may induce cumulative effects resembling acute toxicity. These findings not only highlight the pivotal role of copper homeostasis in CRC pathogenesis but also provide a molecular basis for developing precision therapeutic strategies targeting copper modulation. This underscores the need for establishing individualized copper monitoring systems in clinical interventions. These findings underscore the importance of Cu metabolism homeostasis in maintaining intestinal immune equilibrium and preventing related diseases, warranting further investigation into its underlying mechanisms. Consequently, modulating copper ion homeostasis has emerged as a promising therapeutic approach for both IBD and CRC, demonstrating substantial translational potential. Compared to conventional types of cell death, cuproptosis has garnered interest due to its ability to reprogram the immune microenvironment. Cuproptosis may reshape the immunologic characteristics of the TME, thereby modulating its capacity to inhibit tumor progression and metastatic dissemination [186]. Studies suggest that tumor immunity within the TME can be modulated by cuproptosis [35]. For example, genomic analysis of 1,274 CRC specimens uncovered copper-associated molecular signatures comprising 16 core cuproptosis regulators, establishing a connection between TME heterogeneity and copper dysregulation patterns [187]. Cu-complexed NPs, such as Cu(I)NPs, have been shown to induce cuproptosis, triggering ICD, activating adaptive immune responses, facilitating DC maturation, and boosting CD8+ T-cell infiltration into tumor tissues. This process enhances antitumor immunity and remodels the immune microenvironment [58]. While it is speculated that cuproptosis contributes to shape antitumor immunity, whether Cu-dependent cell death suppresses cancer immunotherapy remains uncertain. Consequently, understanding the pathways of cuproptosis is crucial for progressing innovative combination therapies. Traditional targeted therapies induce the death of malignant cells by disrupting specific cancer-related pathways or molecular targets. Recent medical advances have led to the development of innovative therapeutic strategies and pharmacological agents. For example, the combination of 5-FU and DSF/Cu effectively eliminates CRC cells, LPS-CuS achieves primary CRC eradication through immunophotothermal therapy, and Cu NPs promote tumor antigen presentation and stimulate specific immune responses [34]. Therefore, the dual role of Cu metabolism and cuproptosis presents broad prospects for personalized immunotherapy in IBD and CRC.
As a newly identified mechanism of cellular demise, cuproptosis is undergoing rigorous investigation across diverse disciplines, including chemotherapy, TME regulation, immune-based therapies, and outcome prediction, to develop more effective cancer management strategies. However, the study of cuproptosis is still a nascent field, with current studies primarily focused on its correlation with IBD and CRC. Numerous underlying mechanisms remain to be elucidated, necessitating additional fundamental investigations. Future investigations should focus on deciphering the precise molecular pathways that govern Cu metabolism and cuproptosis in the context of IBD and CRC, as well as explore strategies to modulate Cu levels to maximize therapeutic efficacy. Despite its potential, several challenges remain in cuproptosis research, which also pose obstacles for clinical applications. First, the potential clinical applications and safety concerns related to cuproptosis modulation remain to be fully explored, posing significant challenges for the clinical translation of cuproptosis inducers. Both copper deficiency and excess can induce systemic toxicity, necessitating additional clinical studies to evaluate how copper level modulation affects prognosis in IBD and CRC patients. Such investigations are crucial for improving the targeting efficiency and in vivo stability of these therapeutic agents. Second, Cu's potential as a therapeutic target needs further exploration. This includes developing therapies based on Cu metabolism and cuproptosis, such as gene knockouts and cell-based approaches, while research efforts are shifting toward novel copper inducers, including plant-derived compounds, synthetic molecules, and nanotechnology-based carriers, to improve targeted drug delivery to affected cells. Additionally, the connection between copper metabolism, cuproptosis, and the intestinal immune microenvironment requires further investigation. Combining cuproptosis with immunotherapy could offer a promising strategy to combat IBD and CRC, significantly improving treatment outcomes and extending patient survival. However, it remains unclear whether cuproptosis and its signaling pathways play a protumor role in tumor initiation and development. The current lack of validated cuproptosis biomarkers underscores the need for additional research to enable precision therapeutic interventions. Comprehending the interplay between cuproptosis and alternative forms of cellular demise constitutes another pivotal research domain. Investigating the connections between cuproptosis and other kind of pathways, including apoptosis, ferroptosis, and pyroptosis, may deepen our comprehension of Cu-related diseases and accelerate the progression of targeted therapies to induce tumor cell death more effectively. Looking forward, the discovery of specific biomarkers and personalized antitumor strategies will likely enable the clinical translation of therapies based on Cu metabolism and cuproptosis.
In summary, cuproptosis represents a potential novel therapeutic avenue for IBD and CRC. Advancing understanding of cuproptosis regulation and enhancing its induction efficiency position this pathway as a novel therapeutic strategy for disease intervention. This strategy has the potential not only to suppress disease onset and progression effectively but also to improve patient survival and quality of life through precision therapies. Therefore, understanding the involvement of cuproptosis in pathological processes and developing related treatment strategies holds substantial scientific and medical importance.
Funding
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  • Medical Science and Technology Project of Zhejiang Province(2023RC025)
References
Less
1.
Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–434.
2.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
3.
Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117(5):1137–1146.
4.
Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13(1):3–10.
5.
Jin K, Ren C, Liu Y, Lan H, Wang Z. An update on colorectal cancer microenvironment, epigenetic and immunotherapy. Int Immunopharmacol. 2020;89(Part A): Article 107041.
6.
Roda G, Chien Ng S, Kotze PG, Argollo M, Panaccione R, Spinelli A, Kaser A, Peyrin-Biroulet L, Danese S. Crohn's disease. Nat Rev Dis Primers. 2020;6(1):22.
7.
Kobayashi T, Siegmund B, le Berre C, Wei SC, Ferrante M, Shen B, Bernstein CN, Danese S, Peyrin-Biroulet L, Hibi T. Ulcerative colitis. Nat Rev Dis Primers. 2020;6(1):74.
8.
Wu H, Shen B. Pouchitis: Lessons for inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25(4):314–322.
9.
Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, et al. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study. Lancet. 2016;387(10014):156–167.
10.
Ionescu VA, Gheorghe G, Bacalbasa N, Chiotoroiu AL, Diaconu C. Colorectal cancer: From risk factors to oncogenesis. Medicina (Kaunas). 2023;59(9):1646.
11.
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–1480.
12.
Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: Inflammatory bowel disease and colitis-associated colon cancer. Front Immunol. 2012;3:107.
13.
Xu L, He B, Sun Y, Li J, Shen P, Hu L, Liu G, Wang J, Duan L, Zhan S, et al. Incidence of inflammatory bowel disease in urban China: A nationwide population-based study. Clin Gastroenterol Hepatol. 2023;21(13):3379–3386.e3329.
14.
Wungjiranirun M, Sharzehi K. Wilson's disease. Semin Neurol. 2023;43:626–633.
15.
Türner Z, Horn N. Menkes disease: Recent advances and new insights into copper metabolism. Ann Med. 1996;28(2):121–129.
16.
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254–1261.
17.
Xie J, Yang Y, Gao Y, He J. Cuproptosis: Mechanisms and links with cancers. Mol Cancer. 2023;22(1):46.
18.
da Silva DA, de Luca A, Squitti R, Rongioletti M, Rossi L, Machado CML, Cerchiaro G. Copper in tumors and the use of copper-based compounds in cancer treatment. J Inorg Biochem. 2022;226: Article 111634.
19.
Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, Dou QP, Franz KJ, Gohil VM, Gupta S, et al. Connecting copper and cancer: From transition metal signalling to metalloplasia. Nat Rev Cancer. 2022;22:102–113.
20.
Li Y. Copper homeostasis: Emerging target for cancer treatment. IUBMB Life. 2020;72(9):1900–1908.
21.
Wadhwa S, Mumper RJ. D-penicillamine and other low molecular weight thiols: Review of anticancer effects and related mechanisms. Cancer Lett. 2013;337:8–21.
22.
Lin Q, Hou S, Dai Y, Jiang N, Lin Y. Monascin exhibits neuroprotective effects in rotenone model of Parkinson's disease via antioxidation and anti-neuroinflammation. Neuroreport. 2020;31(9):637–643.
23.
Zhang S, Zong Y, Chen L, Li Q, Li Z, Meng R. The immunomodulatory function and antitumor effect of disulfiram: Paving the way for novel cancer therapeutics. Discov Oncol. 2023;14:103.
24.
Festa RA, Thiele DJ. Copper: An essential metal in biology. Curr Biol. 2011;21(21):R877–R883.
25.
Bost M, Houdart S, Oberli M, Kalonji E, Huneau JF, Margaritis I. Dietary copper and human health: Current evidence and unresolved issue s. J Trace Elem Med Biol. 2016;35:107–115.
26.
Lutsenko S. Dynamic and cell-specific transport networks for intracellular copper ions. J Cell Sci. 2021;134(21):jcs240523.
27.
Lönnerdal B. Intestinal regulation of copper homeostasis: A developmental perspective. Am J Clin Nutr. 2008;88(3):846S–850S.
28.
Doguer C, Ha J, Collins J. Intersection of iron and copper metabolism in the mammalian intestine and liver. Compr Physiol. 2018;8(4):1433–1461.
29.
Migocka M. Copper-transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems. IUBMB Life. 2015;67(10):737–745.
30.
Hernandez S, Tsuchiya Y, García–Ruiz JP, Lalioti V, Nielsen S, Cassio D, Sandoval IV. ATP7B copper-regulated traffic and association with the tight junctions: Copper excretion into the bile. Gastroenterology. 2008;134(1):1215–1223.
31.
Cen D, Brayton D, Shahandeh B, Meyskens FL Jr, Farmer PJ. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem. 2004;47(27):6914–6920.
32.
Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M, du Z, Barsoum J, Bertin J. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther. 2008;7(8):2319–2327.
33.
Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 2014;14(11):709–721.
34.
Wang Y, Chen Y, Zhang J, Yang Y, Fleishman JS, Wang Y, Wang J, Chen J, Li Y, Wang H. Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance. Drug Resist Updat. 2024;72: Article 101018.
35.
Zhang Z, Zeng X, Wu Y, Liu Y, Zhang X, Song Z. Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in hepatocellular carcinoma. Front Immunol. 2022;13:925618.
36.
Yang L, Zhang Y, Wang Y, Jiang P, Liu F, Feng N. Ferredoxin 1 is a cuproptosis-key gene responsible for tumor immunity and drug sensitivity: A pan-cancer analysis. Front Pharmacol. 2022;13:938134.
37.
Fang Y, Tian S, Pan Y, Li W, Wang Q, Tang Y, Yu T, Wu X, Shi Y, Ma P, et al. Pyroptosis: A new frontier in cancer. Biomed Pharmacother. 2020;121: Article 109595.
38.
Tang X, Ren X, Huang T, Miao Y, Ha W, Li Z, Yang L, Mi D. Prognostic and immunological significance of the molecular subtypes and risk signatures based on cuproptosis in hepatocellular carcinoma. Mediat Inflamm. 2023;2023:3951940.
39.
Li Y, Zeng X. A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma. Front Pharmacol. 2023;13:1081952.
40.
Petruzzelli R, Polishchuk RS. Activity and trafficking of copper-transporting ATPases in tumor development and defense against platinum-based drugs. Cells. 2019;8(9):1080.
41.
Xue Q, Kang R, Klionsky DJ, Tang D, Liu J, Chen X. Copper metabolism in cell death and autophagy. Autophagy. 2023;19(8):2175–2195.
42.
Chen J, Jiang Y, Shi H, Peng Y, Fan X, Li C. The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch - Eur J Physiol. 2020;472(10):1415–1429.
43.
Zhang B, Burke R. Copper homeostasis and the ubiquitin proteasome system. Metallomics. 2023;15(3):mfad010.
44.
Tadini-Buoninsegni F, Smeazzetto S. Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B. IUBMB Life. 2017;69(4):218–225.
45.
Zhang H, Shi Y, Yi Q, Wang C, Xia Q, Zhang Y, Jiang W, Qi J. A novel defined cuproptosis-related gene signature for predicting the prognosis of lung adenocarcinoma. Front Genet. 2022;13:975185.
46.
Yagi T, Sawada K, Miyamoto M, Shimizu A, Oi Y, Toda A, Nakamura K, Kinose Y, Kodama M, Hashimoto K, et al. Continuous administration of anti-VEGFA antibody upregulates PAI-1 secretion from ovarian cancer cells via miR-143-3p downregulation. Mol Cancer Res. 2023;21(10):1093–1106.
47.
Nie H, Wang H, Zhang M, Ning Y, Chen X, Zhang Z, Hu X, Zhao Q, Chen P, Fang J, et al. Comprehensive analysis of cuproptosis-related genes in prognosis, tumor microenvironment infiltration, and immunotherapy response in gastric cancer. J Cancer Res Clin Oncol. 2022;149(8):5453–5468.
48.
Huang X, Wang T, Ye J, Feng H, Zhang X, Ma X, Wang B, Huang Y, Zhang X. FDX1 expression predicts favourable prognosis in clear cell renal cell carcinoma identified by bioinformatics and tissue microarray analysis. Front Genet. 2022;13: Article 994741.
49.
Wang L, Cao Y, Guo W, Xu J. High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD). J Cancer Res Clin Oncol. 2023;149(1):15–24.
50.
Wu G, Peng H, Tang M, Yang M, Wang J, Hu Y, Li Z, Li J, Li Z, Song L. ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine. 2021;71: Article 103558.
51.
Mangala LS, Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MMK, Lin YG, et al. Therapeutic targeting of ATP7B in ovarian carcinoma. Clin Cancer Res. 2009;15(11):3770–3780.
52.
Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M, Howell SB. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res. 2004;10(14):4661–4669.
53.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899.
54.
Del Prete A, Schioppa T, Tiberio L, Stabile H, Sozzani S. Leukocyte trafficking in tumor microenvironment. Curr Opin Pharmacol. 2017;35:40–47.
55.
Pottier C, Wheatherspoon A, Roncarati P, Longuespée R, Herfs M, Duray A, Delvenne P, Quatresooz P. The importance of the tumor microenvironment in the therapeutic management of cancer. Expert Rev Anticancer Ther. 2015;15(8):943–954.
56.
Arneth B. Tumor microenvironment. Medicina (Kaunas). 2019;59(1):15.
57.
Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Part 1):1–13.
58.
Hu F, Huang J, Bing T, Mou W, Li D, Zhang H, Chen Y, Jin Q, Yu Y, Yang Z. Stimulus-responsive copper complex nanoparticles induce cuproptosis for augmented cancer immunotherapy. Adv Sci. 2024;11:e2309388.
59.
Ma M, Jiang W, Zhou R. DAMPs and DAMP-sensing receptors in inflammation and diseases. Immunity. 2024;57(4):752–771.
60.
Cheng F, Peng G, Lu Y, Wang K, Ju Q, Ju Y, Ouyang M. Relationship between copper and immunity: The potential role of copper in tumor immunity. Front Oncol. 2022;12:1019153.
61.
Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110:20212–20217.
62.
Lu S, Li Y, Yu Y. Glutathione-scavenging celastrol-Cu nanoparticles induce self-amplified cuproptosis for augmented cancer immunotherapy. Adv Mater. 2024;36(35):e2404971.
63.
Zhao R, Sukocheva O, Tse E, Neganova M, Aleksandrova Y, Zheng Y, Gu H, Zhao D, Madhunapantula SRV, Zhu X, et al. Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: Can it enhance the success of immunotherapy? Cell Commun Signal. 2024;22(1):379.
64.
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799–809.
65.
Cai R, Cheng C, Chen J, Xu X, Ding C, Gu B. Interactions of commensal and pathogenic microorganisms with the mucus layer in the colon. Gut Microbes. 2020;11(4):680–690.
66.
Wu LM, Sankaran SJ, Plank LD, Windsor JA, Petrov MS. Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis. Br J Surg. 2014;101(13):1644–1656.
67.
Puppa MJ, White JP, Sato S, Cairns M, Baynes JW, Carson JA. Gut barrier dysfunction in the ApcMin/+ mouse model of colon cancer cachexia. Biochim Biophys Acta. 2011;1812(12):1601–1606.
68.
Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science. 2004;303(5664):1662–1665.
69.
Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–1273.
70.
Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: Safeguarding barrier function. Nat Rev Gastroenterol Hepatol. 2021;18(8):559–570.
71.
Dolcetti R, De Re V, Canzonieri V. Immunotherapy for gastric cancer: Time for a personalized approach? Int J Mol Sci. 2018;19(6):1602.
72.
Li A, Yi M, Qin S, Song Y, Chu Q, Wu K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy. J Hematol Oncol. 2019;12(1):35.
73.
Zheng J, Mo J, Zhu T, Zhuo W, Yi Y, Hu S, Yin J, Zhang W, Zhou H, Liu Z. Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy. Mol Cancer. 2020;19(1):133.
74.
Liu WQ, Lin WR, Yan L, Xu WH, Yang J. Copper homeostasis and cuproptosis in cancer immunity and therapy. Immunol Rev. 2023;321(1):211–227.
75.
Théry C, Amigorena S. The cell biology of antigen presentation in dendritic cells. Curr Opin Immunol. 2001;13(1):45–51.
76.
Gupta G, Cappellini F, Farcal L, Gornati R, Bernardini G, Fadeel B. Copper oxide nanoparticles trigger macrophage cell death with misfolding of Cu/Zn superoxide dismutase 1 (SOD1). Part Fibre Toxicol. 2022;19(1):33.
77.
Zheng Z, Zhang J, Jiang J, He Y, Zhang W, Mo X, Kang X, Xu Q, Wang B, Huang Y. Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery. J Immunother Cancer. 2020;8(2):e000207.
78.
Gao X, Huang H, Pan C, Mei Z, Yin S, Zhou L, Zheng S. Disulfiram/copper induces immunogenic cell death and enhances CD47 blockade in hepatocellular carcinoma. Cancers (Basel). 2022;14(19):4715.
79.
Chen Y, Cui W, Li X, Yang H. Interaction between commensal bacteria, immune response and the intestinal barrier in inflammatory bowel disease. Front Immunol. 2021;12: Article 761981.
80.
Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol. 2019;16(9):531–543.
81.
Kahlson MA, Dixon SJ. Copper-induced cell death. Science. 2022;375(6586):1231–1232.
82.
Iborra M, Moret I, Rausell F, Bastida G, Aguas M, Cerrillo E, Nos P, Beltrán B. Role of oxidative stress and antioxidant enzymes in Crohn's disease. Biochem Soc Trans. 2011;39(4):1102–1106.
83.
Sahoo DK, Heilmann RM, Paital B, Patel A, Yadav VK, Wong D, Jergens AE. Oxidative stress, hormones, and effects of natural antioxidants on intestinal inflammation in inflammatory bowel disease. Front Endocrinol (Lausanne). 2023;14:1217165.
84.
Pérez S, Taléns-Visconti R, Rius-Pérez S, Finamor I, Sastre J. Redox signaling in the gastrointestinal tract. Free Radic Biol Med. 2017;104:75–103.
85.
Colgan SP, Taylor CT. Hypoxia: An alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol. 2010;7(5):281–287.
86.
Jian Z, Guo H, Liu H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Oxidative stress, apoptosis and inflammatory responses involved in copper-induced pulmonary toxicity in mice. Aging. 2020;12(17):16867–16886.
87.
Gaetke LM, Chow CK. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology. 2003;189(1–2):147–163.
88.
Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, Xu B, Cassidy J, Darling JL, Wang W. Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer. 2011;104(10):1564–1574.
89.
Turski ML, Brady DC, Kim HJ, Kim BE, Nose Y, Counter CM, Winge DR, Thiele DJ. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Mol Cell Biol. 2012;32(7):1284–1295.
90.
Rath E, Moschetta A, Haller D. Mitochondrial function—Gatekeeper of intestinal epithelial cell homeostasis. Nat Rev Gastroenterol Hepatol. 2018;15(8):497–516.
91.
Ho GT, Aird RE, Liu B, Boyapati RK, Kennedy NA, Dorward DA, Noble CL, Shimizu T, Carter RN, Chew ETS, et al. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol. 2018;11(1):120–130.
92.
Jackson DN, Panopoulos M, Neumann WL, Turner K, Cantarel BL, Thompson-Snipes LA, Dassopoulos T, Feagins LA, Souza RF, Mills JC, et al. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis. Gut. 2020;69(11):1928–1938.
93.
Sünderhauf A, Hicken M, Schlichting H, Skibbe K, Ragab M, Raschdorf A, Hirose M, Schäffler H, Bokemeyer A, Bettenworth D, et al. Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis. Cell Mol Gastroenterol Hepatol. 2021;12(1):229–250.
94.
Halliwell B, Gutteridge JMC, Halliwell B, Gutteridge JMC. Antioxidant defences synthesized in vivo. UK: Oxford University Press; 2015.
95.
Candellone A, Cerquetella M, Girolami F, Badino P, Odore R. Acute diarrhea in dogs: Current management and potential role of dietary polyphenols supplementation. Antioxidants. 2020;9(8):725.
96.
Sahoo DK, Chainy GBN. Hormone-linked redox status and its modulation by antioxidants. Netherlands: Elsevier; 2023.
97.
Chainy GBN, Sahoo DK. Hormones and oxidative stress: An overview. Free Radic Res. 2019;54(1):1–26.
98.
Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet. 2017;389(10080):1741–1755.
99.
Choy MC, Visvanathan K, De Cruz P. An overview of the innate and adaptive immune system in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(1):2–13.
100.
de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: An integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14(12):739–749.
101.
Leung CY, Weitz JS. Not by (good) microbes alone: Towards immunocommensal therapies. Trends Microbiol. 2019;27(4):294–302.
102.
Solier S, Müller S, Cañeque T, Versini A, Mansart A, Sindikubwabo F, Baron L, Emam L, Gestraud P, Pantoș GD, et al. A druggable copper-signalling pathway that drives inflammation. Nature. 2023;617(7960):386–394.
103.
Sun R, Chen L. Assessment of heavy metal pollution in topsoil around Beijing Metropolis. PLOS ONE. 2016;11(5): Article e0155350.
104.
Dai J, Yang X, Yuan Y, Jia Y, Liu G, Lin N, Xiao H, Zhang L, Chen J. Toxicity, gut microbiota and metabolome effects after copper exposure during early life in SD rats. Toxicology. 2020;433–434: Article 152395.
105.
Liao J, Li Q, Lei C, Yu W, Deng J, Guo J, Han Q, Hu L, Li Y, Pan J, et al. Toxic effects of copper on the jejunum and colon of pigs: Mechanisms related to gut barrier dysfunction and inflammation influenced by the gut microbiota. Food Funct. 2021;12:9642–9657.
106.
Flemming A. Copper boosts pro-inflammatory state of macrophages. Nat Rev Immunol. 2023;23(6):344.
107.
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.
108.
Qiu W, Wu B, Wang X, Buchanan ME, Regueiro MD, Hartman DJ, Schoen RE, Yu J, Zhang L. PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. J Clin Invest. 2011;121(5):1722–1732.
109.
Klomp AE, van de Sluis B, Klomp LW, Wijmenga C. The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis. J Hepatol. 2003;39(5):703–709.
110.
Maine GN, Burstein E. COMMD proteins: COMMing to the scene. Cell Mol Life Sci. 2007;64(15):1997–2005.
111.
van de Sluis B, Groot AJ, Wijmenga C, Vooijs M, Klomp LW. COMMD1: A novel protein involved in the proteolysis of proteins. Cell Cycle. 2007;6(17):2091–2098.
112.
Maine GN, Mao X, Komarck CM, Burstein E. COMMD1 promotes the ubiquitination of NF-κB subunits through a cullin-containing ubiquitin ligase. EMBO J. 2007;26(2):436–447.
113.
Burstein E, Hoberg JE, Wilkinson AS, Rumble JM, Csomos RA, Komarck CM, Maine GN, Wilkinson JC, Mayo MW, Duckett CS. COMMD proteins, a novel family of structural and functional homologs of MURR1*. J Biol Chem. 2005;280(23):22222–22232.
114.
de Bie P, van de Sluis B, Burstein E, Duran KJ, Berger R, Duckett CS, Wijmenga C, Klomp LWJ. Characterization of COMMD protein–protein interactions in NF-κB signal ling. Biochem J. 398(1):63–71.
115.
Geng H, Wittwer T, Dittrich-Breiholz O, Kracht M, Schmitz ML. Phosphorylation of NF-κB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination. EMBO Rep. 2009;10(4):381–386.
116.
de Bie P, van de Sluis B, Burstein E, Duran KJ, Berger R, Duckett CS, Wijmenga C, Klomp LWJ. Characterization of COMMD protein–protein interactions in NF-κB signalling. Biochem J. 2006;398(1):63–71.
117.
Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, Klomp LWJ, Wijmenga C, Duckett CS, Nabel GJ. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature. 2003;426(6968):853–857.
118.
Li H, Chan L, Bartuzi P, Melton SD, Weber A, Ben–Shlomo S, Varol C, Raetz M, Mao X, Starokadomskyy P, et al. Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer. Gastroenterology. 2014;147(1):184–195 e183.
119.
Zhu H, Li YR. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: Updated experimental and clinical evidence. Exp Biol Med (Maywood). 2012;237(5):474–480.
120.
Pan Q, Bao LW, Merajver SD. Tetrathiomolybdate inhibits angiogenesis and metastasis through suppression of the NFkappaB signaling cascade. Mol Cancer Res. 2003;1(10):701–706.
121.
Xiao J, Guo X, Wang Z. Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: Key clues toward unraveling the mystery. Front Immunol. 2024;15:1385907.
122.
Dengler VL, Galbraith MD, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2013;49(1):1–15.
123.
Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol. 2017;17(12):774–785.
124.
Watts ER, Walmsley SR. Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends Mol Med. 2019;25(1):33–46.
125.
Martin F, Linden T, Katschinski D̈M, Oehme F, Flamme I, Mukhopadhyay CK, Eckhardt K, Tröger J, Barth S, Camenisch G, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: Implications for ceruloplasmin regulation. Blood. 2005;105(12):4613–4619.
126.
Feng W, Ye F, Xue W, Zhou Z, Kang YJ. Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol. 2009;75(1):174–182.
127.
Liu X, Zhang W, Wu Z, Yang Y, Kang YJ. Copper levels affect targeting of hypoxia-inducible factor 1alpha to the promoters of hypoxia-regulated genes. J Biol Chem. 2018;293(38):14669–14677.
128.
Zhang Z, Qiu L, Lin C, Yang H, Fu H, Li R, Kang YJ. Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression. Metallomics. 2014;6(10):1889–1893.
129.
Xie H, Kang YJ. Role of copper in angiogenesis and its medicinal implications. Curr Med Chem. 2009;16(10):1304–1314.
130.
Chen M, Huang Z, Xia M, Ding Y, Shan T, Guan Z, Dai X, Xu X, Huang Y, Huang M, et al. Glutathione-responsive copper-disulfiram nanoparticles for enhanced tumor chemotherapy. J Control Release. 2022;341:351–363.
131.
Tang B, Zhu J, Liu F, Ding J, Wang Y, Fang S, zheng L, Qiu R, Chen M, Shu G, et al. xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade. Cell Death Dis. 2022;13(4):373.
132.
Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov. 2023;22(6):476–495.
133.
Jiménez-Valerio G, Casanovas O. Angiogenesis and metabolism: Entwined for therapy resistance. Trends Cancer. 2017;3(1):10–18.
134.
McAuslan BR, Reilly W. Endothelial cell phagokinesis in response to specific metal ions. Exp Cell Res. 1980;130(1):147–157.
135.
Sivaraja V, Kumar TKS, Rajalingam D, Graziani I, Prudovsky I, Yu C. Copper binding affinity of S100A13, a key component of the FGF-1 nonclassical copper-dependent release complex. Biophys J. 2006;91(5):1832–1843.
136.
Mandinov L, Mandinova A, Kyurkchiev S, Kyurkchiev D, Kehayov I, Kolev V, Soldi R, Bagala C, de Muinck ED, Lindner V, et al. Copper chelation represses the vascular response to injury. Proc Natl Acad Sci USA. 2003;100(11):6700–6705.
137.
Ash D, Sudhahar V, Youn SW, Okur MN, das A, O'Bryan JP, McMenamin M, Hou Y, Kaplan JH, Fukai T, et al. The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2. Nat Commun. 2021;12(1):3091.
138.
Kohno T, Urao N, Ashino T, Sudhahar V, McKinney RD, Hamakubo T, Iwanari H, Ushio-Fukai M, Fukai T. Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury. Arterioscler Thromb Vasc Biol. 2013;33(4):805–813.
139.
Lowndes S, Harris AL. Copper chelation as an antiangiogenic therapy. Oncol Res. 2009;14(11–12):529–539.
140.
Zhang M, Chen L, Wang J. Recent advances in copper chaperone and cancer. Sci Sin Chim. 2018;48(5):1385–1393.
141.
Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat Rev Cancer. 2012;12(8):540–552.
142.
Behrend L, Henderson G, Zwacka RM. Reactive oxygen species in oncogenic transformation. Biochem Soc Trans. 2003;31(Part 6):1441–1444.
143.
Meier B, Radeke HH, Selle S, Younes M, Sies H, Resch K, Habermehl GG. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-α. Biochem J. 1989;263(2):539–545.
144.
Lo YY, Cruz TF. Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. J Biol Chem. 1995;270(20):11727–11730.
145.
Sundaresan M, Yu Z-X, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science. 1995;270(5243):296–299.
146.
Roy D, Sarkar S, Felty Q. Levels of IL-1 beta control stimulatory/inhibitory growth of cancer cells. Front Biosci. 2006;11:889–898.
147.
Baldari S, Di Rocco G, Toietta G. Current biomedical use of copper chelation therapy. Int J Mol Sci. 2020;21(3):1069.
148.
Yoshino H, Yamada Y, Enokida H, Osako Y, Tsuruda M, Kuroshima K, Sakaguchi T, Sugita S, Tatarano S, Nakagawa M. Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma. PLOS ONE. 2020;15(7): Article e0236119.
149.
Rieber M. Cancer pro-oxidant therapy through copper redox cycling: Repurposing disulfiram and tetrathiomolybdate. Curr Pharm Des. 2020;26(35):4461–4466.
150.
Voli F, Valli E, Lerra L, Kimpton K, Saletta F, Giorgi FM, Mercatelli D, Rouaen JRC, Shen S, Murray JE, et al. Intratumoral copper modulates PD-L1 expression and influences tumor immune evasion. Cancer Res. 2020;80(19):4129–4144.
151.
Zhou B, Guo L, Zhang B, Liu S, Zhang K, Yan J, Zhang W, Yu M, Chen Z, Xu Y, et al. Disulfiram combined with copper induces immunosuppression via PD-L1 stabilization in hepatocellular carcinoma. Am J Cancer Res. 2019;9(11):2442–2455.
152.
Baldari S, Rocco GD, Heffern MC, Su TA, Toietta G. Effects of copper chelation on BRAFV600E positive colon carcinoma cells. Cancers. 2019;11(5):659.
153.
Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: A comprehensive review. Front Med. 2021;8:765474.
154.
Kim SM, Hwang IK, Yoo DY, Eum WS, Kim DW, Shin MJ, Ahn EH, Jo HS, Ryu EJ, Yong JI, et al. Tat-antioxidant 1 protects against stress-induced hippocampal HT-22 cells death and attenuate ischaemic insult in animal model. J Cell Mol Med. 2015;19(6):1333–1345.
155.
van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet. 2002;11(2):165–173.
156.
Li H, Burstein E. COMMD1 regulates inflammation and colitis-associated cancer progression. Onco Targets Ther. 2014;3(7): Article e947891.
157.
van de Sluis B, Mao X, Zhai Y, Groot AJ, Vermeulen JF, van der Wall E, van Diest PJ, Hofker MH, Wijmenga C, Klomp LW, et al. COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion. J Clin Invest. 2010;120(6):2119–2130.
158.
Taylor S, Lobo AJ. Diagnosis and treatment of inflammatory bowel disease. Practitioner. 2016;260(1795):19–23.
159.
Ojuawo A, Keith L. The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease. Cent Afr J Med. 2002;48(9-10):116–119.
160.
Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers. 2021;13(5):986.
161.
Heaton DN, George GN, Garrison G, Winge DR. The mitochondrial copper metalochaperone Cox17 exists as an oligomeric, polycopper complex. Biochemistry. 2001;40(3):743–751.
162.
Prohaska JR. Role of copper transporters in copper homeostasis. Am J Clin Nutr. 2008;88(3):826S–829S.
163.
Cobine PA, Pierrel F, Winge DR. Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim Biophys Acta. 2006;1763(7):759–772.
164.
Banci L, Bertini I, Ciofi-Baffoni S, Hadjiloi T, Martinelli M, Palumaa P. Mitochondrial copper(I) transfer from Cox17 to Sco1 is coupled to electron transfer. Proc Natl Acad Sci USA. 2008;105(19):6803–6808.
165.
Singh RP, Jeyaraju DV, Voisin V, Hurren R, Xu C, Hawley JR, Barghout SH, Khan DH, Gronda M, Wang X, et al. Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal. Cell Stem Cell. 2020;26(6):926–937.e10.
166.
Lukanović D, Herzog M, Kobal B, Černe K. The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer. Biomed Pharmacother. 2020;129: Article 110401.
167.
Zhou J, Yu Q, Song J, Li S, Li XL, Kang B, Chen HY, Xu JJ. Photothermally triggered copper payload release for cuproptosis-promoted cancer synergistic therapy. Angew Chem Int Ed Engl. 2023;62(12): Article e202213922.
168.
Jiang PC, Fan J, Zhang CD, Bai MH, Sun QQ, Chen QP, Mao W, Tang BF, Lan HY, Zhou YY, et al. Unraveling colorectal cancer and Pan-cancer immune heterogeneity and synthetic therapy response using cuproptosis and hypoxia regulators by multi-omic analysis and experimental validation. Int J Biol Sci. 2023;19(11):3526–3543.
169.
Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: Current progress and perspectives. J Hematol Oncol. 2021;14(1):85.
170.
Lu S, Tian H, Li B, Li L, Jiang H, Gao Y, Zheng L, Huang C, Zhou Y, du Z, et al. An ellagic acid coordinated copper-based nanoplatform for efficiently overcoming cancer chemoresistance by cuproptosis and synergistic inhibition of cancer cell stemness. Small. 2024;20(17): Article e2309215.
171.
Xia Y, Gu M, Wang J, Zhang X, Shen T, Shi X, Yuan WE. Tumor microenvironment-activated, immunomodulatory nanosheets loaded with copper(II) and 5-FU for synergistic chemodynamic therapy and chemotherapy. J Colloid Interface Sci. 2024;653(Pt A):137–147.
172.
He L, Xu F, Li Y, Jin H, Lo P-C. Cupric-ion-promoted fabrication of oxygen-replenishing nanotherapeutics for synergistic chemo and photodynamic therapy against tumor hypoxia. Acta Biomater. 2023;162:57–71.
173.
Bing J, Zhou B, Chen M, Shen Y, Zhou M, Lin H, Wu W, Shi J. Nanomedicine-enabled concurrent regulations of ROS generation and copper metabolism for sonodynamic-amplified tumor therapy. Biomaterials. 2025;318: Article 123137.
174.
Pashootan P, Saadati F, Fahimi H, Rahmati M, Strippoli R, Zarrabi A, Cordani M, Moosavi MA. Metal-based nanoparticles in cancer therapy: Exploring photodynamic therapy and its interplay with regulated cell death pathways. Int J Pharm. 2024;649: Article 123622.
175.
Dou L, Lu E, Tian D, Li F, Deng L, Zhang Y. Adrenomedullin induces cisplatin chemoresistance in ovarian cancer through reprogramming of glucose metabolism. J Transl Int Med. 2023;11(2):169–177.
176.
Passirani C, Vessières A, La Regina G, Link W, Silvestri R. Modulating undruggable targets to overcome cancer therapy resistance. Drug Resist Updat. 2022;60: Article 100788.
177.
Hendrych M, Říhová K, Adamová B, Hradil V, Stiborek M, Vlček P, Hermanová M, Vašíčková J, Beneš P, Šmarda J, et al. Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma. Biomed Pharmacother. 2022;153: Article 113465.
178.
Wangpaichitr M, Wu C, You M, Maher JC, Dinh V, Feun LG, Savaraj N. N'1,N'3-dimethyl-N'1,N'3-bis(phenylcarbonothioyl) propanedihydrazide (elesclomol) selectively kills cisplatin resistant lung cancer cells through reactive oxygen species (ROS). Cancers. 2009;1(1):23–38.
179.
Buccarelli M, D'Alessandris QG, Matarrese P, Mollinari C, Signore M, Cappannini A, Martini M, D'Aliberti P, de Luca G, Pedini F, et al. Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. J Exp Clin Cancer Res. 2021;40(1):228.
180.
Wang X, Zhou M, Liu Y, Si Z. Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies. Cancer Lett. 2023;561: Article 216157.
181.
Yang W, Wang Y, Huang Y, Yu J, Wang T, Li C, Yang L, Zhang P, Shi L, Yin Y, et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer. Biomed Pharmacother. 2023;159: Article 114301.
182.
Wang H, Zhou X, Li C, Yan S, Feng C, He J, Li Z, Tu C. The emerging role of pyroptosis in pediatric cancers: From mechanism to therapy. J Hematol Oncol. 2022;15(1):140.
183.
Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147(4):742–758.
184.
Kim BE, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol. 2008;4(3):176–185.
185.
Roy U, Gálvez EJC, Iljazovic A, Lesker TR, Błażejewski AJ, Pils MC, Heise U, Huber S, Flavell RA, Strowig T. Distinct microbial communities trigger colitis development upon intestinal barrier damage via innate or adaptive immune cells. Cell Rep. 2017;21(4):994–1008.
186.
Zhang X, Tang B, Luo J, Yang Y, Weng Q, Fang S, Zhao Z, Tu J, Chen M, Ji J. Cuproptosis, ferroptosis and PANoptosis in tumor immune microenvironment remodeling and immunotherapy: Culprits or new hope. Mol Cancer. 2024;23(1):255.
187.
Zhu Z, Zhao Q, Song W, Weng J, Li S, Guo T, Zhu C, Xu Y. A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer. Front Immunol. 2022;13: Article 940774.
188.
Liao J, Yang F, Bai Y, Yu W, Qiao N, Han Q, Zhang H, Guo J, Hu L, Li Y, et al. Metabolomics analysis reveals the effects of copper on mitochondria-mediated apoptosis in kidney of broiler chicken (Gallus gallus). J Inorg Biochem. 2021;224: Article 111581.
189.
Patwa J, Flora SJS. MiADMSA abrogates chronic copper-induced hepatic and immunological changes in Sprague Dawley rats. Food Chem Toxicol. 2020;145: Article 111692.
190.
Skalny AV, Sekacheva MI, Aschner M, Lobanova YN, Tinkov AA. Systemic essential metal and metalloid levels in patients with benign breast disease and breast cancer. Biol Trace Elem Res. 2022;200(12):5003–5012.
191.
Huang Y-L, Sheu J-Y, Lin T-H. Association between oxidative stress and changes of trace elements in patients with breast cancer. Clin Biochem. 1999;32(2):131–136.
192.
Díez M, Arroyo M, Cerdàn FJ, Muñoz M, Martin MA, Balibrea JL. Serum and tissue trace metal levels in lung cancer. Oncology. 1989;46(4):230–234.
193.
Habib FK, Dembinski TC, Stitch SR. The zinc and copper content of blood leucocytes and plasma from patients with benign and malignant prostates. Clin Chim Acta. 1980;104(3):329–335.
194.
Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S. Serum trace elements and Cu/Zn ratio in breast cancer patients. J Surg Oncol. 1991;46(3):178–181.
195.
Sun L, Zhang Y, Yang B, Sun S, Zhang P, Luo Z, Feng T, Cui Z, Zhu T, Li Y, et al. Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer. Nat Commun. 2023;14(1):6523.
196.
Jia X, Tian J, Fu Y, Wang Y, Yang Y, Zhang M, Yang C, Liu Y. Identification of AURKA as a biomarker associated with cuproptosis and ferroptosis in HNSCC. Int J Mol Sci. 2024;25(8):4372.
197.
Zhou Y, Xiao D, Jiang X, Nie C. EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma. J Transl Med. 2023;21(1):28.
198.
Shu T, Wang X. Cuproptosis combines immune landscape providing prognostic biomarker in head and neck squamous carcinoma. Heliyon. 2023;9(5): Article e15494.
199.
Lu H, Zhou L, Zhang B, Xie Y, Yang H, Wang Z. Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma. Front Med (Lausanne). 2022;9: Article 939776.
200.
Lv H, Liu X, Zeng X, Liu Y, Zhang C, Zhang Q, Xu J. Comprehensive analysis of cuproptosis-related genes in immune infiltration and prognosis in melanoma. Front Pharmacol. 2022;13: Article 930041.
201.
Zhao X, Chen J, Yin S, Shi J, Zheng M, He C, Meng H, Han Y, Han J, Guo J, et al. The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis. Front Oncol. 2022;12: Article 992468.
202.
Liu XS, Zeng J, Zhang YH, Zhang Y, Gao Y, Liu C, Pei ZJ. DARS2 is a prognostic biomarker and correlated with immune infiltrates and cuproptosis in lung adenocarcinoma. Am J Cancer Res. 2023;13(3):818–834.
203.
Liu XS, Zhang Y, Liu ZY, Gao Y, Yuan LL, Zeng DB, Tan F, Wan HB, Pei ZJ. METTL3 as a novel diagnosis and treatment biomarker and its association with glycolysis, cuproptosis and ceRNA in oesophageal carcinoma. J Cell Mol Med. 2024;28(6): Article e18195.
204.
Xu L, Wu P, Rong A, Li K, Xiao X, Zhang Y, Wu H. Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker. Aging (Albany NY). 2023;15(10):4269–4287.
205.
Zhang X, Zhou Y, Hu J, Yu X, Xu H, Ba Z, Zhang H, Sun Y, Wang R, du X, et al. Comprehensive analysis identifies cuproptosis-related gene DLAT as a potential prognostic and immunological biomarker in pancreatic adenocarcinoma. BMC Cancer. 2023;23(1):560.
206.
Sun Z, Chen X, Huang X, Wu Y, Shao L, Zhou S, Zheng Z, Lin Y, Chen S. Cuproptosis and immune-related gene signature predicts immunotherapy response and prognosis in lung adenocarcinoma. Life. 2023;13(7):1583.
207.
Li J, Yu T, Sun J, Zeng Z, Liu Z, Ma M, Zheng Z, He Y, Kang W. Comprehensive analysis of cuproptosis-related immune biomarker signature to enhance prognostic accuracy in gastric cancer. Aging (Albany NY). 2023;15(7):2772–2796.
208.
Cai Y, He Q, Liu W, Liang Q, Peng B, Li J, Zhang W, Kang F, Hong Q, Yan Y, et al. Comprehensive analysis of the potential cuproptosis-related biomarker LIAS that regulates prognosis and immunotherapy of pan-cancers. Front Oncol. 2022;12: Article 952129.
209.
Zhou B, Sha S, Wang Q, Sun S, Tao J, Zhu J, Dong L. The prognostic implications of cuproptosis-related gene signature and the potential of PPIC as a promising biomarker in cutaneous melanoma. Pigment Cell Melanoma Res. 2024;37(6):864–880.
210.
Wang X, Chen D, Shi Y, Luo J, Zhang Y, Yuan X, Zhang C, Shu H, Yu W, Tian J. Copper and cuproptosis-related genes in hepatocellular carcinoma: Therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints. Front Immunol. 2023;14:1123231.
211.
Gu Y, Li C, Yan Y, Ming J, Li Y, Chao X, Wang T. Comprehensive analysis and verification of the prognostic significance of cuproptosis-related genes in colon adenocarcinoma. Int J Mol Sci. 2024;25(21):11830.
212.
Fu H, Dong S, Li K. Identification of SLC31A1 as a prognostic biomarker and a target for therapeutics in breast cancer. Sci Rep. 2024;14(1):25120.
213.
Jin Y, Cai S, Zhou Y, Guo D, Zeng Y, Xu W, Sun Y, Shi Y, Xu Z, Liu Z, et al. Targeting SLC7A11/xCT improves radiofrequency ablation efficacy of HCC by dendritic cells mediated anti-tumor immune response. iMeta. 2024;3(6): Article e248.
214.
Bhat AA, Afzal M, Moglad E, Thapa R, Ali H, Almalki WH, Kazmi I, Alzarea SI, Gupta G, Subramaniyan V. lncRNAs as prognostic markers and therapeutic targets in cuproptosis-mediated cancer. Clin Exp Med. 2024;24:226.
215.
Huang X, Hou Y, Weng X, Pang W, Hou L, Liang Y, Wang Y, Du L, Wu T, Yao M, et al. Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway. Oncogenesis. 2021;10(1):4.
216.
Gao W, Huang Z, Duan J, Nice EC, Lin J, Huang C. Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Mol Oncol. 2021;15(12):3527–3544.
217.
Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer. 2003;104(4):504–511.
218.
Hu Y, Qian Y, Wei J, Jin T, Kong X, Cao H, Ding K. The disulfiram/copper complex induces autophagic cell death in colorectal cancer by targeting ULK1. Front Pharmacol. 2021;12:752825.
219.
You S-Y, Rui W, Chen ST, Chen HC, Liu XW, Huang J, Chen HY. Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate. Biochem Biophys Res Commun. 2019;513(4):891–897.
220.
Zuhra K, Panagaki T, Randi EB, Augsburger F, Blondel M, Friocourt G, Herault Y, Szabo C. Mechanism of cystathionine-β-synthase inhibition by disulfiram: The role of bis(N,N-diethyldithiocarbamate)-copper(II). Biochem Pharmacol. 2020;182: Article 114267.
221.
Yang Y, Liang S, Geng H, Xiong M, Li M, Su Q, Jia F, Zhao Y, Wang K, Jiang J, et al. Proteomics revealed the crosstalk between copper stress and cuproptosis, and explored the feasibility of curcumin as anticancer copper ionophore. Free Radic Biol Med. 2022;193(Pt 2):638–647.
222.
Zhang W, Chen C, Shi H, Yang M, Liu Y, Ji P, Chen H, Tan RX, Li E. Curcumin is a biologically active copper chelator with antitumor activity. Phytomedicine. 2016;23(1):1–8.
223.
Barresi V, Spampinato G, Musso N, Trovato Salinaro A, Rizzarelli E, Condorelli DF. ATOX1 gene silencing increases susceptibility to anticancer therapy based on copper ionophores or chelating drugs. J Inorg Biochem. 2016;156:145–152.
224.
Fatfat M, Merhi RA, Rahal O, Stoyanovsky DA, Zaki A, Haidar H, Kagan VE, Gali-Muhtasib H, Machaca K. Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species. BMC Cancer. 2014;14:527.
225.
Shi X, Li Y, Jia M, Zhang Z, Huang L, Zhang M, Xun Q, Jiang D, Liu Y. A novel copper chelator for the suppression of colorectal cancer. Drug Dev Res. 2023;84(2):312–325.
226.
Rolim PM, Fidelis GP, Padilha CEA, Santos ES, Rocha HAO, Macedo GR. Phenolic profile and antioxidant activity from peels and seeds of melon (Cucumis melo L. var. reticulatus) and their antiproliferative effect in cancer cells. Braz J Med Biol Res. 2018;51(4): Article e6069.
227.
Bormio Nunes JH, Hager S, Mathuber M, Pósa V, Roller A, Enyedy ÉA, Stefanelli A, Berger W, Keppler BK, Heffeter P, et al. Cancer cell resistance against the clinically investigated thiosemicarbazone COTI-2 is based on formation of intracellular copper complex glutathione adducts and ABCC1-mediated efflux. J Med Chem. 2020;63(22):13719–13732.
228.
Yu N, Zhu H, Yang Y, Tao Y, Tan F, Pei Q, Zhou Y, Song X, Tan Q, Pei H. Combination of Fe/Cu-chelators and docosahexaenoic acid: An exploration for the treatment of colorectal cancer. Oncotarget. 2017;8(31):51478–51491.
229.
Gandin V, Ceresa C, Esposito G, Indraccolo S, Porchia M, Tisato F, Santini C, Pellei M, Marzano C. Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors. Sci Rep. 2017;7(1):13936.
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Year 2025 volume 8 Issue 5
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Article Info
doi: 10.34133/research.0698
  • Receive Date：2025-03-11
  • Online Date：2025-07-23
  • Published：2025-05-14
Article Data
Affiliations
History
  • Received：2025-03-11
  • Revised：2025-04-07
  • Accepted：2025-04-18
Funding
Medical Science and Technology Project of Zhejiang Province(2023RC025)
Affiliations
    1 Department of Gastroenterology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
    2 China Medical University, Shenyang 110122, China.
    3 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
    4 Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200000, China.
    5 Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou 310007, China.
    6 Department of Nursing, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
    7 Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China.
    8 Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou 310014, China.
    9 Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200000, China.

Corresponding:

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Address correspondence to: (B.T.); (Y.C.); (H.Y.)
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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