Gastric cancer (GC) is one of the most common cancers worldwide particularly in Asian populations, and certain diets have been associated with increased risk of GC. Recent advances in microbial profiling technology have facilitated investigations on microbes residing on the gastric mucosa and increasing evidence has revealed the critical roles of non-Helicobacter pylori gastric microbes in gastric tumorigenesis. On the other hand, diets can affect microbial communities, causing compositional and functional shift of the microbiota. In this review, we summarize the influence of various diets including processed meat, salt-preserved food, high-fat diet, and alcohol on the development and progression of GC. We also explore microbial metabolites and host–microbe interactions in gastric tumorigenesis, alongside dietary interventions targeting the microbiota for the prevention and management against GC.

Mechanical overload is a critical contributor to cartilage degeneration in osteoarthritis (OA) pathogenesis. Circular RNA (circRNA) is expected to provide a long-lasting therapy for OA. However, the involvement of the circRNA-associated competitive endogenous RNA network in chondrocyte senescence induced by mechanical overloading remains unestablished. A mechanical overloading-induced chondrocyte senescence model in human primary chondrocytes is constructed, and differences in the expression of circRNAs and miRNAs were analyzed. The biological roles of circKIAA0586/miR-335-5p in chondrocyte senescence and OA progression under mechanical overloading and its downstream targets were determined using gain- and loss-of-function experiments in various biochemical assays in human chondrocytes. The in vivo effects of circKIAA0586 overexpression were also determined in destabilization of the medial meniscus (DMM) OA mice and aged spontaneous OA mice. The mechanical overloading-induced chondrocyte senescence was aggravated by miR-335-5p or circKIAA0586 knockdown. Accumulated DNA damage response was observed following mechanical overloading, which reduced after miR-335-5p inhibition or circKIAA0586 supplementation. MiR-335-5p was regulated by circKIA0586 adsorption. HELLS was prominently down-regulated following mechanical overloading treatment. Moreover, miR-335-5p bound to lymphoid-specific helicase (HELLS) mRNA during mechanical overloading was demonstrated to mediate the nonhomologous end joining (NHEJ) pathway, thereby inducing DNA damage and senescence. In addition, the senescence delaying and cartilage protective functions of circKIAA0586 and HELLS were validated in DMM OA mice and aged spontaneous OA mice. Our findings suggest that miR-335-5p, which escapes circKIAA0586 adsorption, facilitates mechanical overloading-induced chondrocyte senescence and OA progression by impairing the NHEJ pathway through HELLS inhibition. Overall, targeting circKIAA0586/miR-335-5p/HELLS signaling provides a novel therapeutic approach for OA.

Although equivalent in the infinite-momentum limit, large-momentum effective theory (LaMET) and short-distance operator product expansion (SDE) are 2 very different approaches to obtain parton distribution functions (PDFs) from coordinate-space correlation functions computed in a large-momentum proton through lattice quantum chromodynamics (QCD). LaMET implements a momentum-space expansion in {\mathrm{\Lambda }}_{\mathrm{QCD}}/\left[x\left(1-x\right)P^z\right] to directly calculate PDFs f\left(x\right) in a middle region of Bjorken x\in \left[x_{\min }\sim {\mathrm{\Lambda }}_{\mathrm{QCD}}/{\mathit{xP}}^z,x_{\max }\sim 1-x_{\min }\right]. SDE applies perturbative QCD at small Euclidean distances z to extract a range \left[0,{\lambda }_{\max }\right] of leading-twist correlations, h\left(\lambda ={\mathit{zP}}^z\right), corresponding to the Fourier transformation of PDFs. An incomplete leading-twist correlation from SDE cannot be readily converted to a momentum-space distribution, and solving its constraints on the PDFs (or the so-called “inverse problem”) involves phenomenological modeling of the missing information beyond {\lambda }_{\max } and has no systematic control of errors. I argue that the best use of short-distance correlations is to constrain the PDFs in the LaMET-complementary regions: x\in \left[0,x_{\min }\right] and \left[x_{\max },1\right] through expected end-point asymptotics, and use the results of the pion valence quark distribution from the ANL/BNL collaboration to demonstrate how this can be done.

Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the PML::RARα fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged PML allele rather than the PML::RARα fusion gene. Here, we report that mutations in the unrearranged PML allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged PML allele can confer ATO resistance through a protein–protein interaction. Therefore, the unrearranged PML allele should also be screened for drug-resistant mutations in relapsed APL patients.

DEAD-box ATPase 10 (DDX10), a prominent RNA-binding protein in the DDX family, has a critical function in cancer progression. Nevertheless, its well-defined mechanisms in oral squamous cell carcinoma (OSCC) are still not well understood. Here, we identify that DDX10 is substantially increased in OSCC, which is positively correlated with poor prognosis and malignant behavior. Mechanistically, we found that DDX10 had physical interaction with Rab27b by undergoing phase separation. Knockdown of DDX10 inhibited Rab27b-mediated exosome secretion and the expression of programmed cell death-ligand 1 (PD-L1) within its contents. Furthermore, knocking down DDX10 could restore the function and infiltration of T cells, hence inhibiting the progression of OSCC. These findings highlight that the oncogenic role of DDX10 in promoting exosomal PD-L1 secretion via phase separation with Rab27b has been preliminarily validated in T cell exhaustion in OSCC. A potential strategy for improving OSCC immunotherapy may involve the inhibition of DDX10.

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.

Achieving high maturity and functionality in in vitro skeletal muscle models is essential for advancing our understanding of muscle biology, disease mechanisms, and drug discovery. However, current models struggle to fully recapitulate key features such as sarcomere structure, muscle fiber composition, and contractile function while also ensuring consistency and rapid production. Adult stem cells residing in muscle tissue are known for their powerful regenerative potential, yet tissue-derived skeletal muscle organoids have not been established. In this study, we introduce droplet-engineered skeletal muscle organoids derived from primary tissue using cascade-tubing microfluidics. These droplet-engineered organoids (DEOs) exhibit high maturity, including well-developed striated sarcomeres, spontaneous and stimulated contractions, and recapitulation of parental muscle fiber types. Notably, DEOs are produced in just 8 d without the need for primary cell culture—substantially accelerating the 50- to 60-d process required by classical organoid models. Additionally, the cascade-tubing microfluidics platform enables high-throughput production of hundreds of uniform DEO replicates from a small tissue sample, providing a scalable and reproducible solution for skeletal muscle research and drug screening.

Current strategies for cartilage repair, including decellularized cartilage matrices and synthetic bioactive materials, often encounter challenges such as immune responses and donor morbidity. In this study, we optimized an extracellular matrix (ECM) derived from mesenchymal stem cells through preconditioning with disease-associated inflammatory factors, specifically interleukin 6, tumor necrosis factor alpha, and interferon gamma (IFN-γ). Our in vitro experiments demonstrated that the cytokine-preconditioned stem-cell-derived ECM, especially IFN-γ-ECM, supports chondrocyte homeostasis by restoring mitochondrial energy metabolism. Furthermore, bioactive molecules secreted from this preconditioned ECM boost the recruitment of endogenous stem cells and facilitate their differentiation into chondrocytes. Notably, we found that IFN-γ-ECM facilitates the chondrogenic differentiation of mesenchymal stem cells through the activation of the integrin/phosphatidylinositol 3-kinase/Akt pathway and the Smad2/3 signaling cascade. These results highlight the potential of the cytokine-stimulated ECM, especially IFN-γ-ECM, to restore chondrocyte homeostasis, optimize the mobilization of endogenous stem cells, and substantially improve the regeneration of cartilage defects, offering a promising strategy for acellular cartilage graft reconstruction.

Estrogen fluctuations have been implicated in various mood disorders, including perimenopausal and postpartum depression (PPD), likely through complex neural networks. γ-aminobutyric acid-ergic (GABAergic) neurons in the medial preoptic area (MPOA) that express estrogen receptor 1 (ESR1) are essential for the development and expression of depressive-like behaviors in ovarian hormone withdrawal (HW) mice. However, the precise circuit mechanisms through which MPOA GABAergic neurons influence behavior remain incompletely understood. Here, we identified robust projections from MPOA GABAergic neurons to the paraventricular nucleus of the hypothalamus (PVN). In HW mice, chemogenetic activation of MPOA GABAergic neurons targeting PVN attenuated depressive-like behaviors. Conversely, in nonhormone withdrawal (NHW) control mice (which received continuous estrogen), suppression of MPOA GABAergic projections to PVN exacerbated depressive-like behaviors. Further analyses using quantitative polymerase chain reaction and immunostaining identified arginine vasopressin (AVP) as a key neuropeptide in this pathway in the HW mouse model. Chemogenetic inhibition of PVN^AVP neurons significantly alleviated depressive-like behaviors in HW mice, while their activation in NHW mice worsened depressive-like behaviors. These behaviors were dependent on AVP expression in PVN^AVP neurons. Moreover, in HW mice, chemogenetic inhibition of PVN^AVP neurons receiving MPOA input mitigated depressive-like behaviors. Conversely, in NHW mice, activation of these neurons exacerbated depressive-like behaviors. Electrophysiological recordings demonstrated that MPOA GABAergic neurons directly inhibit PVN^AVP neurons. Thus, our findings suggest that PVN^AVP neurons serve as downstream effectors of MPOA GABAergic neurons via monosynaptic inhibitory signaling to regulate depressive-like behaviors. Targeting this circuit may offer a novel therapeutic strategy for PPD.

The disruption of ferroptosis, an emerging form of programmed cell death, is crucial in the development and aggressiveness of tumors. Meanwhile, the mechanisms and treatments that control ferroptosis in neuroblastoma (NB), a prevalent extracranial cancer in children, are still unknown. In this study, forkhead box C1 (FOXC1) and O-GlcNAc transferase (OGT) are identified as regulators of asparagine- and alanine-mediated ferroptosis repression in NB. Mechanistically, OGT facilitates FOXC1 stabilization via inducing O-GlcNAcylation in liquid condensates to increase the expression of asparagine synthetase (ASNS) and glutamate pyruvate transaminase 2 (GPT2), resulting in asparagine and alanine biogenesis, and subsequent synthesis of cystathionine β-synthase (CBS) or ferritin heavy chain 1 (FTH1). Meanwhile, exonic circular OGT RNA (ecircOGT) is able to encode a novel protein (OGT-570aa) containing domain essential for binding of OGT to FOXC1, which competitively decreases the OGT–FOXC1 interaction. Preclinically, miconazole nitrate facilitates the interaction of OGT-570aa with FOXC1, suppresses ferroptosis resistance of NB cells, and inhibits their growth, invasion, and metastasis. In clinical NB cases, higher OGT, FOXC1, ASNS, GPT2, CBS, or FTH1 levels are correlated with worse survival, while lower ecircOGT or OGT-570aa expression is associated with tumor progression. These results indicate that targeting the ecircOGT/OGT/FOXC1 axis inhibits asparagine- and alanine-mediated ferroptosis repression in NB progression.