Triple-negative breast cancer (TNBC) is characterized by high metastatic tendency and poor prognosis, largely driven by dynamic crosstalk between cancer cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a major component of the TME, yet their functional contributions to TNBC progression remain incompletely understood. In this study, we isolated exosomes from patient-derived CAFs and normal fibroblasts (NFs), and profiled their circRNA content using RNA sequencing. circFAD104 was significantly enriched in CAFs and their derived exosomes, with elevated stromal expression confirmed by qRT-PCR and in situ hybridization (ISH). PKH26 labeling demonstrated that CAF-derived exosomes efficiently deliver circFAD104 to TNBC cells, where it enhances cancer stemness, metastasis, and glycolysis. Mechanistically, circFAD104 acts as a molecular scaffold to promote the interaction between the E3 ubiquitin ligase MARCHF8 and its substrate PGM1, facilitating MARCHF8-mediated K48-linked ubiquitination and subsequent proteasomal degradation of PGM1. Loss of PGM1 redirects glucose flux from glycogen synthesis toward glycolysis, thereby fueling tumor progression. Clinically, high circFAD104 levels were correlated with poorer overall survival in breast cancer patients. These findings uncover a CAF-exosomal circFAD104 axis that reprograms glucose metabolism to drive TNBC progression via the circFAD104/MARCHF8/PGM1 pathway, highlighting its potential as a stroma-targeted biomarker and prognostic predictor.

Temozolomide (TMZ) remains the first-line therapy for glioblastoma (GBM) patients. However, the mechanisms underlying the emergence of acquired TMZ resistance after treatment are unclear. Here, we reveal the critical role of macrophage phagocytosis in GBM recurrence and acquired TMZ resistance. Mechanistically, TMZ treatment sustained GSK3β activation and promoted its interaction with DNMT1. This led to the phosphorylation of DNMT1 at the previously unrecognized S977 site for its K981-dependent ubiquitination and destabilization. The downregulation of DNMT1 leads to hypomethylation of the CD47 promoter and increases the expression of CD47, a key inhibitor of macrophage phagocytosis. Elevated CD47 expression suppresses macrophage phagocytosis and promotes the survival of TMZ-treated GBM cells. The small molecule WIN 51708 disrupts the p-GSK3β-Y216-DNMT1 interaction, which stabilizes DNMT1, decreases CD47 expression, restores phagocytosis in vivo, and resensitizes tumors to TMZ. The GSK3β-DNMT1-CD47 axis was found to be conserved in a TMZ-resistant PDX model and in samples from patients with recurrent GBM, supporting its clinical translational value. Our findings underscore the potential of the combined administration of WIN 51708 and TMZ as a strategy to resensitize GBM tumors.

Maternal obesity (MO) impairs immunological development in the offspring with poorly defined mechanisms. By integrating single-cell RNA sequencing datasets from placentas and fetal livers of diet-induced obese mice, data showed that MO markedly enhances inflammatory and immune activation within the placenta but induces immunosuppression in fetal liver. Inter-organ cell-cell communication analysis further revealed that placental Spp1 signaling sent by macrophage potentiates TGFβ/Smad signaling in fetal liver immune cells, which promotes Rbl2 upregulation and induces a G1 phase arrest in T cells and basophils. Finally, T cell function is inhibited by MO. Totally, this study identifies a potential placental-fetal liver Spp1-TGFβ-Rbl2 axis associated with fetal immunosuppression due to MO.

Graves' disease (GD) is the most common cause of autoimmune hyperthyroidism, and stress has long been implicated in its onset. Whether stress genuinely triggers thyroid autoimmunity or is an epiphenomenon of evolving hyperthyroidism remains unclear. This systematic review appraised original observational studies examining the association between psychological and physiological stress and the onset and clinical course of GD. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, MEDLINE/PubMed, Embase, Scopus, Web of Science, PsycINFO and the Cochrane Library were searched from database inception to June 19, 2026. Eligible studies were original case-control or cohort investigations assessing stress exposure with validated instruments in patients with confirmed GD relative to a control or comparison group. Reviews, case reports, conference abstracts, and preprints were excluded. Methodological quality was appraised with the Newcastle-Ottawa Scale (NOS), a validated nine-point instrument for non-randomized studies rating selection, comparability, and exposure or outcome ascertainment, with predefined thresholds used to classify risk of bias. Certainty of evidence was rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Substantial heterogeneity in exposure instruments, comparators, and outcome metrics precluded meta-analysis, so the evidence was synthesized narratively. Thirteen studies, enrolling at least 2,867 participants and including 1,134 patients with confirmed GD, met the eligibility criteria. Most retrospective case-control studies reported a significantly higher burden of negative life events in the 12 months preceding GD diagnosis than in controls, with large effect estimates and a female-predominant association. Where patients with non-autoimmune toxic nodular goitre served as comparators, the excess was confined to the autoimmune group. Three studies linked stress to disease recurrence and to a poorer response to antithyroid drug therapy, again chiefly in women. Conversely, the prospective cohort and a chronic endogenous stress study found no association with de novo thyroid autoimmunity or incident GD. Overall certainty of evidence was very low, principally because of the predominantly retrospective designs with attendant recall bias and reverse causation, inconsistency between retrospective and prospective findings, and imprecision from small samples. Retrospective evidence supports an association between antecedent stress and GD onset and, to a lesser extent, its course in genetically predisposed individuals, particularly women, while the limited prospective evidence is inconsistent with this association. Adequately powered prospective cohort studies employing standardised stress instruments and objective stress biomarkers are needed before a causal role can be affirmed.

The gut and liver form an anatomical and functional unit linked by the portal circulation, the biliary tract, lymphatic drainage, and neuroimmune pathways. In recent years, the classical gut-liver axis has expanded from a predominantly microbial and metabolic concept into a broader framework in which immune cells are viewed as central integrators of inter-organ signaling. In health, balanced microbial sensing, intact mucosal and vascular barriers, regulated bile acid signaling, and specialized tissue-resident immune programs preserve tolerance at both intestinal and hepatic interfaces. In disease, dysbiosis, barrier failure, altered bile acid pools, endogenous hepatotoxic metabolites, and aberrant immune-cell trafficking remodel the hepatic immune niche and drive steatohepatitis, alcohol-associated liver injury, cholangiopathy, cirrhosis, acute decompensation, and hepatocellular carcinoma. This review reframes the gut-liver axis as a gut-liver-immune axis and synthesizes current evidence on its structural basis, cellular architecture, molecular mediators, and disease-specific manifestations. We discuss the roles of macrophages, dendritic cells, neutrophils, innate-like T cells, natural killer cells, and adaptive T-cell subsets in translating gut-derived signals into hepatic inflammation, tissue repair, fibrosis, or tumor surveillance. We also highlight the bidirectional role of the liver in shaping intestinal immunity, particularly through bile acids and hepatobiliary-derived mediators. Finally, we examine current therapeutic strategies targeting the microbiota, mucosal barrier, bile acid signaling, and immune-cell trafficking, and we outline major conceptual and translational gaps that should guide the next generation of mechanistic and clinical studies.

[This corrects the article DOI: 10.3389/fimmu.2026.1864805.].

The interplay between host immunity and the microbiome is increasingly recognized as an important factor in ocular surface diseases. Although cutaneous and intestinal dysbiosis have been implicated in atopic dermatitis (AD), the role of the ocular microbiome in its severe ophthalmic manifestation, atopic keratoconjunctivitis (AKC), remains incompletely understood.

Cardiovascular disease is a major complication of chronic kidney disease (CKD) and often develops alongside skeletal muscle wasting and sarcopenia. These abnormalities are usually studied as separate consequences of CKD, but they may also be linked through shared systemic stressors and inter-organ communication. CKD exposes both skeletal muscle and the myocardium to a persistent uremic milieu characterized by toxin retention, chronic inflammation, oxidative stress, hypoxia, and metabolic disturbance. In this setting, skeletal muscle-heart crosstalk may shift from an adaptive homeostatic program to a maladaptive network that contributes to myocardial metabolic dysfunction and fibrotic remodeling. Under physiological conditions, and especially during exercise, skeletal muscle releases myokines and extracellular vesicles carrying miRNAs, proteins, and other regulatory molecules that support myocardial substrate utilization, mitochondrial function, and repair responses. In CKD, however, altered myokine profiles and dysregulated extracellular vesicle cargoes may act on cardiomyocytes, cardiac fibroblasts, and endothelial cells, promoting impaired metabolic flexibility, extracellular matrix deposition, and progressive cardiac remodeling. The heart may also feed back on skeletal muscle through cardiac-derived endocrine signals and neurohumoral pathways, further reinforcing muscle wasting and systemic dysfunction. In this review, we summarize current evidence on skeletal muscle-heart communication under physiological, exercise-related, and CKD-associated conditions, with emphasis on myokines, extracellular vesicles, and miRNA-mediated signaling. Better definition of this axis may help identify biomarkers and therapeutic targets for CKD-associated sarcopenia and cardiovascular disease.

Preserved Ratio Impaired Spirometry (PRISm) is a spirometric phenotype characterized by a FEV1/FVC ratio ≥ 0.7 and FEV1 < 80% of the predicted value. It is significantly associated with increased all-cause mortality and the risk of various diseases. However, its underlying pathophysiological mechanisms remain incompletely understood. By synthesizing evidence from epidemiological and mechanistic studies, this review proposes the "inflammatory-metabolic axis" as the central pathogenic mechanism driving PRISm. This theoretical framework posits that inflammaging establishes a pro-inflammatory substrate, which, upon amplification by exogenous stimuli, culminates in a self-sustaining chronic inflammatory network. Concurrently, metabolic dysfunction interacts synergistically with inflammatory processes via pro-oxidative mechanisms and dysregulated adipokine signaling. PRISm thus represents an early functional pulmonary manifestation of systemic inflammatory-metabolic dysregulation. This review underscores that targeting inflammatory-metabolic interactions offers a promising translational avenue for the early identification and intervention of PRISm.

As a complex airway inflammatory disease, the pathogenesis of asthma is closely associated with dynamic changes in the lung microbiome and immune regulation. Asthmatic patients with distinct inflammatory phenotypes exhibit significant alterations in the diversity and dominant microbiota of their lung microbiome, particularly characterized by the colonization of bacteria such as Haemophilus influenzae, Moraxella catarrhalis, and Tropheryma whipplei. The microbial community modulates the differentiation of CD4+ T-cell subsets and activates or inhibits inflammatory pathways, thereby exerting interactive effects on the eosinophilic and neutrophilic inflammatory phenotypes of asthma. Microbial products, such as lipopolysaccharide (LPS), exosomes, and bacterial lysates, play crucial roles in activating or suppressing host immune cells, mediating the initiation and progression of airway inflammation. Current studies have primarily elucidated the mechanisms by which the lung microbiome modulates asthma immune regulation and explored immunomodulatory strategies targeting microorganisms and their products, including the potential of bacterial lysates, probiotic therapy, and microbial exosome therapy in asthma. Unlike previous reviews focusing on the gut-lung axis, this review establishes correspondences between specific bacterial species and distinct asthma endotypes, and critically evaluates the methodological heterogeneity in this field. These reflections provide a theoretical basis for standardizing microbiome research, elucidating microbiota-driven differential progression of asthma subtypes, and advancing microbiome-based precision prevention strategies.

Incomplete radiofrequency ablation (iRFA) exposes residual hepatocellular carcinoma (HCC) cells to sublethal thermal stress, which triggers metabolic adaptations that support cell survival. In this study, we demonstrate that iRFA significantly enhances glucose uptake in HCC cells, contributing to the suppression of intracellular reactive oxygen species (ROS) and promoting cell viability. Mechanistically, this effect is mediated by the translocation of GLUT4 from the cytoplasm to the plasma membrane, rather than changes in total GLUT4 expression. GLUT4 redistribution under thermal stress facilitates rapid glucose uptake, providing energy and biosynthetic intermediates necessary for survival under adverse microenvironmental conditions. Inhibition of GLUT4-mediated glucose uptake increases ROS accumulation and reduces cell survival, highlighting its critical role in redox homeostasis. Collectively, our findings reveal an iRFA-GLUT4-glucose uptake axis as a key metabolic adaptation pathway that enables residual tumor cells to survive sublethal thermal stress, suggesting that targeting GLUT4 dynamics may represent a potential therapeutic strategy to improve the efficacy of iRFA and prevent tumor recurrence.

Ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, critically contributes to ischemic stroke (IS) pathophysiology through iron overload, glutathione depletion, and dysregulation of the System Xc-/GPX4 axis. This review systematically evaluates natural product-derived interventions targeting ferroptosis for IS management. A systematic search of PubMed, Web of Science, and ScienceDirect from their inception through May 22, 2026 identified 74 eligible studies. Our synthesis reveals three core mechanistic hubs: (1) restoring iron homeostasis by regulating ferritinophagy and iron transporters; (2) suppressing lipid peroxidation by targeting the ACSL4/LPCAT3 cascade and activating Nrf2/HO-1 signaling; and (3) reinforcing antioxidant defenses through upregulation of the System Xc-/GSH/GPX4 pathway. The reviewed interventions encompass six major classes of natural products-including flavonoids, terpenoids, saponins, phenolic acids, phenylpropanoids, and alkaloids-and multi-herb formulas such as Buyang Huanwu Decoction and Naotaifang. Collectively, these agents reduce malondialdehyde (MDA) levels while elevating superoxide dismutase (SOD) and glutathione (GSH) activities in preclinical models. Crucially, we identify persistent translational bottlenecks, including poor pharmacokinetic profiles, undefined blood-brain barrier permeability, uncharacterized active constituents in herbal formulas, and a distinct lack of clinical validation. These findings establish that while natural compounds robustly inhibit ferroptosis in experimental models, bridging the translational gap requires rigorous standardization and high-quality clinical trials to fulfill their therapeutic potential.

Metabolic reprogramming is a central feature of many human diseases, and therapies that target altered metabolic dependencies are moving from concept to clinical testing. Amino acid homeostasis links essential and nonessential amino acid supply with branched-chain amino acid (BCAA) catabolism, one-carbon metabolism, mechanistic target of rapamycin complex 1 (mTORC1)/general control nonderepressible 2 (GCN2) nutrient sensing, glutathione-dependent redox control, epigenetic regulation, and the gut microbiota-amino acid axis. When this network is disturbed, amino acid flux can contribute to disease initiation and progression rather than simply mirroring established pathology. This review synthesizes how amino acid metabolism supports the nervous, cardiovascular, digestive, metabolic-endocrine, immune, skeletal, urinary and reproductive systems, as well as malignant and inherited metabolic disorders. We also examine how pathway-level disturbances converge on excitotoxicity, endothelial dysfunction, insulin resistance, inflammation, fibrosis, immune escape, toxic metabolite accumulation, and impaired fertility. Rather than catalog isolated findings, we emphasize unifying principles and unresolved controversies, including the context-dependent effects of BCAA signaling, the causal versus biomarker status of circulating amino acid signatures, host-gut microbiome crosstalk, and the therapeutic window of dietary, enzymatic, transporter-targeted, and microbiota-based interventions. Finally, we assess clinical translation, drawing lessons from late-stage trial failures and emerging strategies with realistic potential for precision metabolic therapy.