Ischemic stroke (IS) results from an acute interruption of cerebral blood flow and the ensuing collapse of energy metabolism. Although vascular recanalization can salvage the ischemic penumbra, its overall benefit remains constrained by a narrow therapeutic window and reperfusion injury. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to neuronal injury after IS and can amplify ischemia/reperfusion injury. By integrating energy metabolism, iron homeostasis, and redox balance, mitochondria can shape ferroptosis susceptibility within the energy-depleted, iron-dysregulated, and oxidatively stressed ischemic brain. However, most studies have examined iron metabolism and lipid peroxidation at the whole-cell level, leaving the temporal and interorganelle dimensions of mitochondrial regulation of ferroptosis insufficiently integrated. Here, we organize mitochondria-associated ferroptosis across the pathological course of IS, from metabolic reprogramming and substrate accumulation during ischemia to the reverse electron transport-associated reactive oxygen species burst during early reperfusion and subsequent disruption of mitochondrial quality control. We further examine mitochondrial crosstalk with the endoplasmic reticulum, lysosomes, lipid droplets, and nucleus, compare ferroptosis susceptibility across neurovascular unit cell populations, and map these mechanisms onto pharmacological interventions and mechanistically plausible therapeutic windows. Finally, we assess barriers to the clinical translation of mitochondria-targeted therapies and provide a stage-resolved framework for developing neuroprotective strategies in IS.

A highly branched α-glucan, designated GE0A, was isolated from Galli Gigeriae Endothelium Corneum and investigated for its structural characteristics, gastrointestinal fate, and metabolic effects in diet-induced obesity. GE0A had a weight-average molecular weight of 85.0kDa and consisted exclusively of glucose. Methylation and NMR analyses revealed a branched α-glucan composed predominantly of α-(1→4)-linked glucopyranosyl sequences with O-6 branch points. During simulated digestion, GE0A remained stable in salivary and gastric phases but was partially depolymerized into lower-molecular-weight oligosaccharides during the intestinal phase. Following oral administration, Cy5-labeled GE0A-derived material remained largely confined to the gastrointestinal tract, reached the cecum and colon, and showed partial association with F4/80-positive intestinal macrophages. During in vitro fecal fermentation, GE0A-derived carbohydrates were efficiently utilized by gut microbiota, accompanied by microbial growth and increased acetate and propionate production. In high-fat diet-fed mice, oral GE0A reduced body-weight gain without altering food intake, attenuated adipose accumulation and hepatic steatosis, improved glucose and lipid homeostasis, and enhanced cold tolerance and brown-adipose UCP1 and TOMM20 expression. GE0A also alleviated systemic and tissue inflammation, oxidative stress, and PI-positive damaged cells. Antibiotic-mediated microbiota depletion largely attenuated these metabolic and thermogenic benefits, whereas transplantation of microbiota from GE0A-treated donors was associated with partial recovery of several metabolic responses, supporting a microbiota-dependent mechanism. Collectively, these findings indicate that GE0A behaves as a fermentable dietary-fiber-like α-glucan that undergoes partial intestinal depolymerization and is subsequently utilized by gut microbiota to generate short-chain fatty acids associated with improved metabolic homeostasis.

Tumor-immune cell crosstalk critically shapes the progression of non-small cell lung cancer (NSCLC), yet the mechanisms underlying exosome-mediated immune suppression remain incompletely understood. Here, we identify a previously unrecognized exosomal lncRNA-mediated immunoregulatory axis targeted by the natural compound Ophiopogonin D (OP-D). Transcriptomic profiling and mechanistic rescue experiments revealed that Lewis lung carcinoma (LLC)-derived exosomal MALAT1 suppresses dendritic cell (DC) maturation by increasing SIRT1 expression and attenuating p65 phosphorylation. Computational modeling combined with molecular dynamics simulation predicted a stable interaction between OP-D and MALAT1, which was further validated by biolayer interferometry (BLI) and microscale thermophoresis (MST) assays, supporting MALAT1 as a direct molecular target of OP-D. In vivo, OP-D markedly inhibited tumor growth and enhanced intratumoral DC activation. Mechanistically, OP-D reduced MALAT1 abundance in LLC-derived exosomes and decreased the accumulation of exosomal MALAT1 in recipient DCs, thereby suppressing SIRT1 signaling, restoring p65 phosphorylation, and promoting DC maturation and antitumor immune responses. Furthermore, MALAT1 overexpression attenuated the immunostimulatory effects of OP-D, confirming the functional importance of the exosomal MALAT1-SIRT1/p-p65 axis. Collectively, these findings identify exosomal MALAT1 as a critical mediator of tumor-induced DC dysfunction and establish OP-D as a promising immunomodulatory natural compound capable of reprogramming tumor-immune communication in NSCLC.

Aflatoxins (AFs), toxic secondary metabolites primarily produced by Aspergillus flavus and A. parasiticus, remain a serious global health challenge due to both acute and particularly chronic toxicity. Unlike acute toxicity, chronic low-dose exposure to AFs is insidious and cumulative, leading to long-term effects such as immune dysfunction, growth retardation, and carcinogenesis. These outcomes are often underestimated, underscoring the importance of preventive strategies over therapeutic interventions. Although pharmacological agents have been investigated to inhibit CYP450-mediated bioactivation or enhance detoxification, their efficacy remains limited, particularly in reversing established damage. To address these limitations, recent efforts have shifted toward mechanism-based protective strategies, including interventions that block aflatoxin B1 (AFB1) activation, enhance detoxification, and restore host defense. Recent evidence indicates that phytochemicals and probiotics exert promising multimodal activities, including attenuation of oxidative stress, inhibition of DNA adduct formation, and restoration of gut-microbiota-immune balance. For example, carnosic acid has a good free radical scavenging capacity, kolaviron could suppress abnormal DNA synthesis, and Bifidobacterium breve BAA-2849 may mitigate AFB1-induced injury partly through gut microbiota remodeling and barrier protection. Furthermore, novel materials capable of adsorbing AFs can mitigate intoxication by reducing AFs levels. In this review, we critically synthesize advances in AFs toxicology and detoxification strategies, with particular emphasis on underlying mechanisms. We highlight probiotics and novel materials that detoxify or reduce AFs, proposing them as promising candidates for future research aimed at propelling therapeutic strategies. By identifying research gaps and outlining translational prospects, this review seeks to guide the development of effective and clinically applicable pharmacological strategies to mitigate AFs-associated health risks.

Reticulon-3 (RTN3) was initially studied as an endoplasmic reticulum (ER)-resident reticulon family protein involved in membrane shaping, apoptosis, and amyloid precursor protein processing. More recent work has considerably expanded this view and now places RTN3 at the intersection of ER remodeling, selective ER-phagy, cargo trafficking, lipid handling, and stress signaling. This shift is especially relevant to pharmacology, because RTN3 appears to exhibit heterogeneous effects across tissues and disease states: RTN3 upregulation is maladaptive in obesity, nonalcoholic fatty liver disease, cardiac lipotoxicity, post-myocardial infarction heart failure, and some vascular conditions, whereas RTN3 loss aggravates renal injury, renal fibrosis, and pulmonary fibrosis. Viral infection and hepatocellular carcinoma further illustrate that RTN3 can either support membrane remodeling programs or constrain disease progression, depending on the biological environment. In this review, we reorganize RTN3 biology around mechanism-driven processes and discuss how these processes converge on cardiometabolic, fibrotic, infectious, and oncologic phenotypes. Current evidence suggests that RTN3 is better regarded as a membrane organizing regulator with therapeutic potential rather than a disease specific marker. However, future efforts to target RTN3 will likely need to consider tissue type and pathway specificity.

Cisplatin resistance in hepatoblastoma (HB) is a major therapeutic barrier. Emerging evidence suggests that cancer cells can activate DNA double-strand break repair pathways to evade chemotherapy-induced apoptosis and sustain stemness; however, the mechanisms underlying cisplatin resistance in HB remain poorly understood. Here, we identified the neuronal protein BEX4 as a key mediator of cisplatin resistance. BEX4 was aberrantly overexpressed in HB cells and maintained a stem-like state. Mechanistically, BEX4 bound to and stabilized the core nonhomologous end-joining (NHEJ) factor X-ray repair cross-complementing protein 5 (XRCC5), thereby promoting NHEJ activity and contributing to cisplatin resistance. DNA damage induced ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of BEX4 at Thr107, promoting transient dissociation of the BEX4-XRCC5 complex and facilitating XRCC5 recruitment to DNA damage sites. BEX4-driven NHEJ enhances DNA damage repair, potentially contributing to genomic instability, stemness, and chemoresistance. Building on these mechanistic findings, we identified a small-molecule compound, F35-303, which disrupted the BEX4-XRCC5 interaction, suppressed NHEJ activity, and restored cisplatin sensitivity in resistant preclinical models. Our findings identify BEX4 as a key mediator of cisplatin resistance in HB and suggest that targeting the BEX4-XRCC5 interaction with F35-303 may provide a new therapeutic strategy for overcoming chemoresistance in HB and a mechanistic framework for understanding adaptive chemoresistance.

Meteorin-like (Metrnl) is a newly discovered multifunctional secreted protein widely expressed in various tissues such as adipose tissue, skeletal muscle, and epithelial barrier tissues. This review systematically summarizes current knowledge of Metrnl, detailing its molecular characteristics, structure, cellular sources, inducers, receptors, and the complex signaling pathways and network. Metrnl has been identified as a pleiotropic protein with multiple effects, including enhancing insulin sensitivity, modulating lipid metabolism, promoting neurogenesis, reducing inflammation and oxidative stress, regulating tumor immunity, and potentiating angiogenesis and tissue repair. In metabolic and endocrine disorders, cardiovascular and cerebrovascular diseases, respiratory diseases, gastrointestinal diseases, skin diseases, autoimmune diseases, and nervous system diseases, and other pathological processes, the expression of Metrnl shows tissue-specific and disease stage-dependent changes, underscoring its potential as a biomarker or novel therapeutic target. However, the expression characteristics and biological functions of Metrnl in some diseases are controversial, and its tissue-specific role has not been fully elucidated. This review integrates clinical cohort studies and animal model results targeting Metrnl and its receptors. On this basis, we propose that Metrnl should be regarded as a stress-responsive immunometabolic molecule rather than a static disease biomarker. The research on targeted intervention in Metrnl is currently in the preclinical stage and has not yet progressed to clinical trials, and its clinical application value in specific diseases needs to be verified by large-scale stratified cohort analysis. This article aims to provide theoretical clues and novel insights for understanding Metrnl as a potential biomarker and therapeutic target.

Rheumatoid arthritis (RA) is a systemic immune-mediated disease in which persistent synovial inflammation contributes not only to joint destruction but also to cardiovascular, pulmonary, metabolic, and other extra-articular complications. This review focuses specifically on the translational potential of emerging receptor-directed pro-resolving therapeutics in targeting persistent inflammation, a common mechanism driving RA and its systemic comorbidities. Although contemporary disease-modifying antirheumatic drugs (DMARDs) have substantially improved disease control and structural outcomes, a complementary therapeutic question remains: can the endogenous biological program that terminates inflammation and restores tissue homeostasis be therapeutically engaged? Resolution pharmacology addresses this question by targeting endogenous pro-resolving pathways involving specialized pro-resolving mediators (SPMs), annexin A1 (AnxA1), melanocortin receptors, the formyl peptide receptor 2 (FPR2/ALX), and related signalling networks. This review examines the evidence linking defective resolution with RA and critically evaluates the therapeutic potential of resolution-directed interventions across articular disease and major RA-associated comorbidities. Rather than treating resolution pharmacology as a uniform therapeutic class, we distinguish anti-inflammatory effects from demonstrated pro-resolving activities and evaluate evidence ranging from in vitro and animal studies to observational human studies and clinical trials. This review particularly emphasizes receptor selectivity, biased agonism, and their use in combination with established DMARD therapies. We propose that the principal opportunity for resolution pharmacology is not to replace effective DMARD therapy but to complement it, promoting inflammatory termination and tissue recovery. Thus, resolution pharmacology should currently be considered a promising translational framework requiring future clinical validation rather than an established therapeutic paradigm for RA and its comorbidities.

Hutchinson-Gilford progeria syndrome (HGPS) is characterized by progressive vascular injury that remains incompletely controlled by therapies targeting progerin-associated pathology. Here, we investigated the therapeutic activity and molecular mechanisms of melatonin-preconditioned mesenchymal stromal cell-derived small extracellular vesicles (MT-Exo) using a patient-anchored translational framework integrating longitudinal vascular phenotyping and serial serum samples from an index patient with HGPS with independently sourced HGPS fibroblasts and endothelial-cell models. Serial HGPS serum samples exhibited increased progerin and cellular prion protein (PrPᶜ) signals, together with elevated troponin I, in the setting of progressive multisite vasculopathy. HGPS serum impaired endothelial morphology and angiogenic network formation, whereas recombinant PrPᶜ induced cellular-stress, inflammatory, chromatin, and nuclear-lamina abnormalities. MT-Exo attenuated HGPS serum-induced endothelial dysfunction and reduced progerin, PrPᶜ, p16, and γH2AX abnormalities and lamin A/C disorganization in HGPS fibroblasts. Mechanistically, MT-Exo-enriched miR-4651 directly targeted SRSF1 and attenuated progerin-associated nuclear-lamina abnormalities, whereas MT-Exo-enriched miR-6126 directly targeted SP1 and reduced PRNP/PrPᶜ expression. These two microRNAs therefore acted through distinct but complementary regulatory pathways involving SRSF1-progerin and SP1-PRNP/PrPᶜ signaling. A prespecified patient-informed virtual-cohort analysis of 15 treatment strategies further prioritized a cluster of lonafarnib-based combinations containing MT-Exo, dual miRNA, or miR-6126 for subsequent experimental evaluation, although no single regimen was consistently top-ranked across models. Collectively, these findings identify complementary miR-4651-SRSF1-progerin and miR-6126-SP1-PRNP/PrPᶜ regulatory axes in HGPS vascular aging and provide a mechanistic rationale for preclinical evaluation of MT-Exo- and miRNA-based combination strategies.

Lung metastasis is a major cause of cancer-related mortality, and the pre-metastatic niche (PMN) provides a window for early intervention. Here, transcriptomic profiling of pre-metastatic lungs in a subcutaneous B16-F10 melanoma model identified S100a8 and S100a9 as strongly upregulated PMN-associated genes. Exploratory TCGA analyses further linked high S100A8 or S100A9 expression with poorer overall survival in selected cancer types, although most associations were attenuated after multivariable adjustment. To evaluate these molecules as vaccine targets, we engineered recombinant fusion proteins linking mouse S100A8, S100A9, or tandem S100A8/A9 to a hypervariable-region-deleted flagellin (FliCΔHP) that retains Toll-like receptor 5 agonist activity. All three fusion proteins broke immune tolerance and elicited high-titer antigen-specific IgG responses, whereas only FliCΔHP-A9 significantly reduced experimental pulmonary metastasis in both male and female mice. Among the analyzed animals, anti-S100A9 IgG titers were inversely associated with metastatic burden. Immune serum inhibited S100A9-driven B16-F10 migration in vitro, and passive transfer of FliCΔHP-A9 immune serum reduced lung metastatic burden in naïve recipients, supporting an important contribution of humoral immunity to protection. Vaccination was also associated with lower pulmonary S100a8/S100a9 expression, reduced granulocytic and monocytic myeloid-derived suppressor cell accumulation, increased CD8[+] T-cell frequencies, and an IFN-γ/IL-12-enriched pulmonary immune environment. Collectively, these findings identify S100A9 as an effective vaccine target in this experimental setting and suggest that S100A9-directed humoral immunity is accompanied by remodeling of the pulmonary immune microenvironment. Validation in spontaneous metastasis models and translational systems will be required to define the broader therapeutic potential of FliCΔHP-A9.

Cancer stem cells (CSCs) drive tumor recurrence, metastasis, and therapeutic resistance.Rather than exhibiting a uniform glycolytic phenotype, CSCs occupy tumor- and state-dependent metabolic configurations ranging from glycolysisdominant to oxidative phosphorylation（OXPHOS）-dependent and hybrid states. In hypoxic and hypoxia-inducible factor-1α（HIF-1α）-active CSC subpopulations, aerobic glycolysis can support stemness, treatment resistance, and immune evasion by increasing glucose consumption, lactate production, and microenvironmental acidification. Accordingly, the HIF-Warburg axis represents an actionable but context-dependent metabolic vulnerability. This review systematically examines nanodrug design strategies targeting the HIF-Warburg axis, spanning four regulatory levels: (1) Direct inhibition of HIF-1α expression via nanocarriers delivering siRNA or oxygen-releasing particles; (2) Inhibition of glycolysis through nanoscale inhibitors targeting HK2, LDHA, and PDK1; (3) Substrate deprivation by targeting GLUT1 or employing glucose oxidase; and (4) Lactate neutralization and pH-responsive nanosystems to reverse the acidic microenvironment, reactivate immune responses, and achieve metabolic-immune synergistic therapy. This review synthesizes interactions among CSCs, the Warburg effect, HIF-1α signaling, and immune evasion mechanisms, and highlights emerging nanotherapeutic strategies that exploit these vulnerabilities to improve cancer treatment outcomes, offering significant promise for advancing precision cancer therapy.

Sepsis-induced cardiomyopathy (SICM) is an acute, often reversible myocardial depression driven by the host response to infection. Cardiac macrophages are central signaling hubs that integrate systemic danger signals and orchestrate myocardial dysfunction. We introduce a "Macrophage Functional Continuum" model, conceptualizing macrophages as dynamic signal integrators undergoing three interconnected phases: sensing and initiation, intrinsic reprogramming and fate determination, and multicellular network execution. Conceptually, these phases represent functional modules that may overlap in time and vary across organs, rather than a rigid chronological sequence. Stage-matched strategies-including immunometabolic modulation, checkpoint control, nanomedicine, and macrophage-based therapies-may provide a more context-sensitive therapeutic framework than conventional anti-inflammatory approaches. This review aims to reframe macrophage biology in SICM and provide a roadmap for translational research.

Advanced glycation end-products (AGEs) accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD); however, the contribution of individual AGE species remains poorly defined. We focused on Nε-(carboxymethyl)lysine (CML), a well-characterised AGE generated through glycoxidation and lipid peroxidation, and investigated its association with steatotic liver disease and its effects in multicellular liver models. AGE-RAGE pathway activity was analysed in public liver transcriptomic cohorts, and total AGEs and CML were quantified in human liver and serum. Free CML was then used as a defined experimental stimulus in mice, HepG2 2D/3D, and human induced pluripotent stem cell-derived liver organoid (HLO) models. AGE-RAGE pathway activity was associated with steatohepatitis-related features, whereas hepatic CML was selectively elevated in steatotic liver. Oral CML induced AGE-RAGE- and transforming growth factor beta-associated transcriptional changes in mice but minimal histological fibrosis, whereas HepG2 models showed limited CML-associated lipid accumulation. In contrast, HLOs exhibited concentration-dependent lipid accumulation and fibrogenic remodelling. Single-cell and functional analyses further revealed coordinated mitochondrial stress, inflammatory activation, stellate-cell remodelling, and collagen deposition. Selected responses were attenuated by pathway-targeted interventions, and patient serum cytokine and liver proteomic profiles showed partial concordance with HLO-associated signatures. Together, these findings identify hepatic CML as an AGE-related feature of steatotic liver disease and demonstrate coordinated mitochondrial, inflammatory, and fibrogenic responses to CML in multicellular HLOs. These results support the utility of HLOs for investigating AGE-specific mechanisms in human liver pathology.