Pomelo (Citrus maxima cv. Wentan) peel represents a major agricultural byproduct rich in pectin with potential applications in functional foods and biomedical materials. This study aimed to elucidate the structure–activity relationship of pomelo peel pectin extracted at different temperatures (100 to 140 °C) and to evaluate its neuro–gut protective effects using a zebrafish model. Pectins obtained under varying thermal conditions were structurally characterized, and their bioactivities were systematically compared. Among them, pectin extracted at 130 °C (P-130) exhibited higher galacturonic acid content, molecular weight, and hydroxyl group abundance. Functionally, P-130 effectively mitigated bisphenol AF-induced toxicity in zebrafish. It significantly improved developmental outcomes, reduced oxidative stress, and preserved neuronal integrity by promoting axonal growth and up-regulating neurodevelopment-related genes. Notably, P-130 regulated the gut–brain axis by restoring neurotransmitter balance (5-hydroxytryptamine and dopamine), attenuating intestinal inflammation, and modulating gut microbiota composition, particularly by enriching beneficial taxa such as Bacteroidetes. These effects were associated with reduced anxiety-like behavior. Histopathological analyses further confirmed its protective roles in cerebellar and intestinal tissues. This study highlights the critical influence of extraction temperature on pectin structure and identifies P-130 as a promising natural agent against environmental toxicants. The findings provide novel insights into the synergistic mechanisms linking antioxidant activity, neuroprotection, and microbiota regulation, offering a scientific basis for the valorization of pomelo peel in developing plant-derived protective strategies.

Immune regulation is essential in both the pathogenesis and treatment of various diseases. Plant-derived extracellular-vesicle-like particles (PDEVLPs), especially herbal medicine, are emerging as promising cross-species nanotherapeutic carriers for immune regulation due to their intrinsic bioactive components. Compared with traditional small-molecule drugs, these natural nanocarriers offer superior pharmacokinetic properties in mammalian systems, including enhanced targeting capacity and penetration efficiency as well as prolonged circulation time. Due to the biogenic structures and low immunogenicity, most PDEVLPs exhibit generally favorable biocompatibility and substantial advantages in specific contexts. However, their immunological profile in humans, particularly the risk of immunogenicity from heterologous plant proteins, requires further investigation compared to established platforms such as liposomes. While diverse active ingredients endow PDEVLPs with effective regulation of various immune cells, they support body homeostasis and offer marked potential for treating multifactorial inflammatory and immune-related diseases. This review examines disease-specific immune microenvironments to provide a theoretical foundation for selecting PDEVLP-based therapies. It also evaluates engineering strategies to enhance the targeted delivery and therapeutic efficacy of these interkingdom mediators. By summarizing recent advancements, this review aims to guide the development of next-generation immune regulatory carriers tailored to specific microenvironments.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)-mediated type I interferon response plays a crucial role in antitumor immunity, yet the regulatory factors involved in this innate immune response remain incompletely understood. Here, we identified methyltransferase-like 3 (METTL3), an RNA N⁶-methyladenosine methyltransferase, as a key suppressor of the cGAS/STING pathway in lung adenocarcinoma (LUAD) cells. METTL3 was overexpressed in LUAD tissues, and elevated METTL3 expression was associated with decreased CD8⁺ T-cell infiltration and poor clinical outcomes. Mechanistically, METTL3 deficiency promoted nuclear DNA leakage into the cytoplasm, thereby activating the cGAS pathway and enhancing antitumor immunity. Specifically, METTL3 knockdown decreased the efficiency of homologous recombination repair by down-regulating MutS homolog 5, leading to cytosolic DNA accumulation. On the other hand, N⁶-methyladenosine methylation of cGAS messenger RNA destabilized the transcript and suppressed its protein expression. Functionally, METTL3 knockdown sensitized LUAD cells to poly(ADP-ribose) polymerase inhibitors. In vivo and clinical data confirmed the beneficial effects of METTL3-inhibition-induced activation of the cGAS/STING axis on tumor growth and LUAD progression. Collectively, our findings reveal that METTL3 inhibition activates cGAS/STING-mediated antitumor immunity by inducing cytosolic DNA accumulation and cGAS up-regulation, thereby modulating poly(ADP-ribose) polymerase inhibitor response and cancer progression in LUAD.

This study sought to investigate the link between sleep disorders and cardiac microvascular injury in myocardial ischemia–reperfusion injury (MI/RI) mice. Mice were subjected to a sleep deprivation protocol within a designated chamber. During the light phase (ZT0 to ZT12), a sweep bar moved across the cage floor at 2-min intervals, whereas it remained static throughout the dark phase (ZT12 to ZT24), with this routine maintained for 16 weeks. Subsequently, an MI/RI model was established to assess the extent of cardiac microvascular injury, and the underlying mechanisms were explored via proteomic analyses. It was demonstrated that 16 weeks of sleep fragmentation (SF) intensified cardiac microvascular damage in MI/RI mice. From a mechanistic perspective, SF was found to induce sympathetic hyperactivity, elevate plasma epinephrine levels, and consequently facilitate neutrophil chemotaxis and the generation of neutrophil extracellular traps (NETs). Moreover, the findings revealed that NETs suppressed Atox1 expression, impaired ATP7A-mediated copper transport, and contributed to copper accumulation within cardiac microvascular endothelial cells (CMECs) and oxidative stress. This copper overload further augmented cuproptosis, while these pathological alterations were shown to be reversible through sympathetic denervation, vagal electrical stimulation (ES), targeted delivery of copper chelators, or the inhibition of NETs. Overall, our data established that SF exacerbated MI/RI by promoting copper overload in CMECs. This study elucidated a molecular pathway through which sleep disturbances aggravated cardiac microvascular damage and suggested prospective targets for treatment strategies.

Diffuse large B cell lymphoma (DLBCL) presents a critical clinical challenge due to declining chemosensitivity and difficult-to-manage dose-limiting toxicities. Although gut microbiota modulation shows potential for “toxicity reduction and efficacy enhancement”, its mechanism in DLBCL remains unclear. Comparative analysis revealed a marked reduction of beneficial bacteria in patients with DLBCL versus healthy volunteers, with a marked decrease in the abundance of core probiotics, particularly Limosilactobacillus reuteri. Fecal microbiota transplantation from healthy donors into DLBCL mouse models reduced tumor burden, improved chemosensitivity, and alleviated intestinal toxicity. A core probiotic strain, L. reuteri HG001, was isolated and shown to replicate these effects alone, with the tryptophan metabolite indole-3-carbaldehyde (ICAld) identified as the key component responsible for its adjunctive antitumor activity. Mechanistic studies demonstrated that ICAld exerts significant adjunctive antitumor effects both in vitro and in vivo in a dose-dependent manner in mouse models; it acts by activating the aryl hydrocarbon receptor (AHR)/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/reactive oxygen species (ROS) axis, inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway, promoting apoptosis, and synergizing with cyclophosphamide. An aryl hydrocarbon receptor antagonist reversed both the chemosensitizing and intestinal protective effects of L. reuteri HG001 and ICAld. This study elucidates a microbiota-mediated mechanism in DLBCL and supports L. reuteri HG001 as a probiotic adjuvant to enhance therapy while reducing toxicity.

Terahertz (THz) waves occupy a unique spectral region where they can resonantly interact with collective vibrational modes of biomolecules, thereby modulating protein conformation and subsequently affecting neural signaling. However, whether noninvasive THz wave stimulation can be extended to Alzheimer’s disease and related dementias (ADRD) remains unknown. Here, we demonstrate that 14 d of noninvasive THz wave binocular stimulation (33 THz) effectively restores cognitive performance and neural homeostasis in Aβ_1–42-induced dementia mice, a widely used experimental model of ADRD with the features including neuroinflammation and cognitive decline. Behavioral assessments revealed a marked restoration of spatial learning and memory ability, with a 53.1% ± 22.0% improvement compared with untreated dementia mice. Furthermore, THz wave stimulation reduced sleep fragmentation and restored physiological sleep–wake dynamics, indicating improved neural homeostasis. In the hippocampus, binocular stimulation attenuated microglial activation and normalized the levels of pro-inflammatory cytokines including interleukin-1β and tumor necrosis factor-α. Concurrently, THz wave stimulation activated hippocampal cyclic adenosine monophosphate (cAMP)–cAMP-response element binding protein (CREB)–brain-derived neurotrophic factor (BDNF) signaling, promoting neurotrophic support and re-establishing cholinergic functional integrity. Our findings demonstrate that THz wave binocular stimulation is a noninvasive approach capable of improving cognitive function in a dementia mouse model, offering a potential strategy to restore brain function in neurodegenerative diseases.

Hydroxyl radicals (•OH) generated under redox fluctuations in paddy soils are crucial for biogeochemical processes. Artificial humic acid (A-HA), as an emerging soil amendment, has been widely applied to improve soil quality. However, the impacts of A-HA on •OH generation and biogeochemical consequences remain under-explored. This study investigated the effects of A-HA on •OH generation, revealing that A-HA enhanced •OH accumulation from 43.93 to 142.30 μM upon oxygenation. The 0.5 M HCl-extracted Fe(II) was the dominant driver for •OH production via H₂O₂ as an intermediate. Multi-omics analyses demonstrated that A-HA reshaped the microbial community from a sulfate-reducing state to a copiotrophic state dominated by iron-reducing and fermentative bacteria. By acting as an electron shuttle and accelerating intermediate metabolism, A-HA overcame Fe(III) reduction kinetic barriers, providing a thermodynamic advantage that competitively suppressed sulfate-reducing bacteria. Additionally, •OH-induced mineralization and adsorption/fractionation by Fe(III)(oxyhydr)oxides decreased the content of dissolved organic matter (DOM). Fourier transform ion cyclotron resonance mass spectrometry confirmed that “saturated and oxidized” compounds were enriched during anaerobic incubation and subsequently preferentially degraded by •OH through dealkylation, decarboxylation, and oxygen addition, revealing a complementary pattern between anaerobic enrichment and oxidative degradation. Machine learning identified N/C, S/C, m/z, and O/C as key predictors of DOM transformation susceptibility, aligning with the metabolic enrichment of nitrogenous pathways. Furthermore, the enhanced •OH degraded propanil with a removal rate of up to 56.54%, suggesting that contaminants adsorbed on mineral surfaces were more susceptible to degradation. This study revealed a coupled mechanism in which microbial metabolic regulation during reduction enhances iron reduction for subsequent abiotic oxidation, providing new insights into microbial iron reduction, organic matter, and contaminant transformation in paddy ecosystems. Overall, these results further emphasized that A-HA substantially impacts paddy environments far beyond improving soil fertility.

Sensory neurons act as crucial hubs for host defense, tumor immunity, and tissue homeostasis by detecting environmental cues and fine-tuning immune responses. Across a diversity of tissues, these neurons establish specialized neuroimmune units with resident immune cells, translating local stimuli into coordinated physiological adaptations. Central to this crosstalk is calcitonin gene-related peptide (CGRP). Released by activated sensory neurons, CGRP dynamically governs immune cell function, neurogenic inflammation, and tissue repair. This review synthesizes current evidence establishing CGRP as a master regulator of neuroimmune communication. We dissect its highly context-dependent roles in microbial infections, the tumor microenvironment, and barrier tissues, emphasizing how microbial identity, spatial niches, and concurrent signaling cues dictate its functional outcomes. Mechanistically, we explore the molecular cascades through which diverse cell types decode CGRP signals, focusing on receptor subtype selectivity and cell-specific adaptor switching. Furthermore, we evaluate emerging therapeutic strategies targeting the CGRP axis—ranging from small-molecule modulators to monoclonal antibodies—and their transformative potential for treating immune-mediated conditions, from chronic inflammation to malignancies. Ultimately, we identify critical knowledge gaps, such as the “CGRP receptor code” and neuromicrobial feedback loops, which must be resolved to fully harness the therapeutic promise of this neuroimmune axis.

Breast cancer remains the most common malignancy in women worldwide, and its marked heterogeneity continues to impede effective treatment. Immunotherapy has reshaped the therapeutic landscape, yet only a subset of patients achieves durable benefit, in large part because of immune and metabolic diversity within the tumor microenvironment. Posttranslational modifications are key regulators that couple cellular signaling to metabolic and immune homeostasis. Here, we generated a multiomics immune-metabolic atlas of breast cancer by integrating genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics from 115 tumor and 99 matched adjacent tissue samples. Using immune infiltration profiling, we defined 3 immune-related breast cancer subtypes with distinct metabolic states, posttranslational modifications cross-talk, and mutational landscapes. Integrated analyses revealed that the interplay between protein lactylation and phosphorylation orchestrates glycolytic reprogramming and immune modulation. Furthermore, we identified subtype-specific histone lactylation patterns and signaling rewiring associated with therapeutic response. This atlas provides a comprehensive framework for dissecting immune-metabolic regulation in breast cancer and yields molecular insights to guide subtype-specific precision immunotherapeutic strategies.

Brown adipose tissue (BAT) plays a crucial role in maintaining energy balance and regulating glucose and lipid metabolism. Preserving BAT activity has been considered a potential strategy to mitigate metabolic dysfunctions such as diet-induced obesity (DIO). Here, we identified a pronounced copper overload in the BAT of DIO mice. Normalization of copper levels through copper chelation or cold exposure effectively restored the expression of the thermogenic effector protein UCP1, prevented BAT whitening, and improved systemic metabolic parameters. Proteomic profiling revealed ATP-citrate lyase (ACLY)—a key enzyme in acetyl-CoA synthesis and de novo lipogenesis—as a critical mediator in BAT copper homeostasis. ACLY expression was down-regulated in BAT of DIO mice but increased in cold-challenged or copper-chelated BAT. Loss of ACLY promoted NRF2 acetylation and nuclear translocation, leading to the transcriptional repression of the copper chaperone ATOX1, which exacerbated copper accumulation in BAT, resulting in BAT whitening and dysfunction. Connectivity Map screening identified succinylsulfathiazole (SST) as an upstream activator of ACLY expression. Both in vitro and in vivo administration of SST restored ACLY expression, corrected copper dysregulation, and re-established BAT activity. Collectively, these findings uncover a mechanism linking ACLY to copper homeostasis in BAT and highlight SST as a promising repurposed candidate for correcting obesity and BAT dysfunction-associated metabolic disorders.