BackgroundAlcohol-induced osteonecrosis of the femoral head (AIONFH) is associated with impaired bone formation and increased bone cell apoptosis. This study investigated the role of osteoclast-derived exosomal miR-378a-3p and the FTO-mediated m6A pathway in AIONFH.MethodsRat bone marrow-derived macrophages (BMMs) were induced to form osteoclasts with or without ethanol. Exosomes were isolated, and differentially expressed miRNAs were identified by sequencing and RT-qPCR. The interaction between miR-378a-3p and FTO was examined using a dual-luciferase reporter assay. The effects of modified osteoclast-derived exosomes on BMSC osteogenic differentiation, apoptosis, FTO expression, and m6A levels were evaluated under ethanol exposure. An AIONFH rat model was used to assess the therapeutic effects of these exosomes in vivo.ResultsEthanol promoted osteoclast formation and reduced miR-378a-3p levels in osteoclast-derived exosomes. miR-378a-3p directly targeted the FTO 3′-UTR and reduced FTO expression. Under ethanol exposure, FTO expression increased, m6A levels decreased, osteogenic differentiation was inhibited, and apoptosis was increased. miR-378a-3p-enriched exosomes reversed these changes by reducing FTO expression, increasing m6A levels, promoting osteogenesis, and reducing apoptosis. In AIONFH rats, these exosomes improved trabecular bone structure, increased osteogenic marker expression, and reduced femoral head apoptosis. Exosomes with miR-378a-3p inhibition produced opposite effects.ConclusionOsteoclast-derived exosomal miR-378a-3p protects against alcohol-induced bone damage by targeting FTO and regulating m6A modification. The miR-378a-3p/FTO/m6A pathway may be a potential therapeutic target for AIONFH.
Aortic dissection (AD) is an emergent medical condition with a hidden onset and sudden rupture, which usually results in a high mortality rate. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNA molecules and plays a critical role in regulating RNA metabolism. Dysregulation of m6A modification has been linked to a variety of diseases. Interestingly, aberrant expression of m6A-associated factors is observed in AD. The m6A methylation can promote or inhibit the development of AD by modulating cell death, oxidative stress, macrophage polarization and VSMC phenotype switching, depending on m6A-modified transcripts, readers and downstream pathways. In addition, m6A exerts a significant effect on the major risk factors for AD, including hypertension, atherosclerosis, obesity and aortic aneurysm. Thus, modulating m6A modification by small-molecule inhibitors, natural products or miRNAs may represent a promising approach for developing new therapeutic interventions for AD. In this review, we first give a brief perspective on m6A modification and its regulators. Subsequently, we summarize the recent research progress on the role of m6A in AD and related-risk factors, with an emphasis on its diagnostic value and therapeutic potential.
Cardiovascular–kidney–metabolic (CKM) syndrome represents a systemic disease continuum arising from the progressive and reciprocal interactions among metabolic dysfunction, kidney injury, and cardiovascular disease. Obesity and type 2 diabetes mellitus (T2DM) are major metabolic drivers of early CKM progression and contribute to cardiac and kidney injury through insulin resistance, glucotoxicity and lipotoxicity, chronic inflammation, oxidative stress, mitochondrial dysfunction, and ectopic lipid deposition, thereby establishing a self-reinforcing vicious cycle across the metabolic, cardiovascular, and renal systems. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) not only participate in the regulation of glucose homeostasis and energy metabolism but also represent an important regulatory nexus linking metabolic dysfunction to cardiorenal injury. GLP-1 receptor agonists (GLP-1RAs) improve metabolic homeostasis by enhancing glucose-dependent insulin secretion, suppressing glucagon release, reducing appetite and body weight, and decreasing visceral and ectopic fat accumulation. In parallel, they may exert renal and cardiovascular protective effects by improving endothelial function and microcirculation, suppressing inflammation and oxidative stress, maintaining mitochondrial homeostasis, and attenuating fibrosis. In recent years, large-scale clinical studies have further extended the benefits of GLP-1RAs beyond glycaemic control and weight reduction to improved kidney outcomes, reduced major cardiovascular events, and benefits in obesity-related heart failure with preserved ejection fraction. Meanwhile, natural products, characterised by multi-component, multi-target, and multi-pathway actions, may provide a complementary strategy for integrated CKM management by simultaneously improving glucose and lipid metabolic disturbances, insulin resistance, inflammation, and oxidative stress, while attenuating cardiac remodelling, kidney injury, and fibrosis. Emerging studies have shown that some natural products can concurrently improve metabolic, cardiac, and renal phenotypes in CKM-related diseases or composite disease models. This review focuses on the interactions among the metabolic, renal, and cardiovascular systems in CKM, summarises the biological basis and signalling mechanisms of the GLP-1/GLP-1R system, and highlights the mechanistic and clinical evidence supporting GLP-1RA-mediated protection against obesity- and T2DM-related metabolic dysfunction and cardiorenal injury. The potential value of natural products in comprehensive CKM intervention and future research directions are also discussed.
Osteoarthritis (OA) is one of the most common degenerative joint diseases, and its clinical burden arises not only from degenerative changes and synovial inflammation but is also closely associated with chronic pain, functional impairment, and reduced quality of life. In patients with OA, imaging-detected structural damage and pain severity are not always consistent, suggesting that symptom persistence may also be driven by mechanisms such as metabolic disturbance, inflammatory amplification, and neural sensitization. Existing evidence indicates that mitochondrial abnormalities can be observed in cartilage, synovium, subchondral bone, and sensory nerve-related compartments, but the strength of evidence and the causal hierarchy differ across compartments. In chondrocytes, disruption of mitochondrial homeostasis is often accompanied by imbalanced energy metabolism, oxidative stress, impaired quality control, and mtDNA damage, and is associated with cell aging, regulated cell death, and matrix degeneration. Mitochondrial stress in other joint and neural compartments may participate in local inflammation, abnormal bone remodeling, and peripheral and central pain sensitization. Mitochondria-derived DAMPs, and inflammatory mediators may mediate cross-compartment interactions, but current evidence is insufficient to establish a continuous causal chain from cartilage degeneration unidirectionally to pain sensitization. Therefore, mitochondria in OA are more appropriately regarded as a pathological network shared across multiple tissue compartments and potentially interacting with one another. Building on this perspective, this article takes pain sensitization as an important dimension for understanding structural damage and symptoms in OA, and uses the “metabolism-senescence-pain axis” as a hypothesis-generating framework to review the role of mitochondrial dysfunction in OA structural degeneration, cell aging, regulated cell death, and pain sensitization, with emphasis on distinguishing evidence across cartilage, synovium, subchondral bone, sensory neurons, and central nervous system-related compartments, and to discuss potential cross-compartment interactions mediated by DAMPs, and neuroimmune signaling. Furthermore, by integrating human, animal, in vitro, and translational studies, the existing evidence is stratified, and the progress and translational barriers of mitochondria-directed and related therapeutic strategies are summarized. Finally, this article proposes future directions such as cell type-specific delivery, mitochondrial biomarkers, candidate pain mechanism phenotypes, and composite “mechanism-symptom-structure” endpoints, thereby offering a foundation for dissecting mechanistic heterogeneity, patient stratification, and precision intervention in OA.
BackgroundAtherosclerotic plaque progression couples chronic inflammation to dysregulated cell survival, but the cellular context and regulatory role of endoplasmic reticulum (ER)-associated death responses in human carotid disease remain incompletely resolved.MethodsWe integrated paired bulk transcriptomes from 32 carotid plaque and macroscopically intact tissue pairs, laser-captured macrophages from five ruptured and six stable plaques, whole-plaque transcriptomes from 27 intraplaque-hemorrhage and 16 non-hemorrhage lesions, and single-cell RNA sequencing from three patients with matched atherosclerotic core and proximal adjacent tissue. BCAP31 was evaluated by siRNA-mediated depletion in oxidized low-density lipoprotein (oxLDL)-exposed THP-1-derived macrophages, with PCR, immunofluorescence, ELISA, apoptosis assays, and 4-phenylbutyrate treatment.ResultsPaired bulk analysis showed coordinated increases in apoptosis, ferroptosis, pyroptosis, necroptosis, inflammasome, inflammatory-response, and TNF/NF-κB programs. Ruptured plaque macrophages showed increases in ferroptosis, pyroptosis, and necroptosis scores, whereas intraplaque-hemorrhage plaques showed broader activation across all prespecified programs. Patient-level single-cell pseudobulk analysis localized a directionally consistent increase in BCAP31 to macrophages, although the estimate did not remain significant after transcriptome-wide correction in the three-patient dataset. Cross-sectional state ordering placed higher BCAP31 expression toward plaque-enriched HLA-C1QC, APOC1-SPP1-remodeling, and SPP1-lipid-loaded macrophage states, while predicted macrophage-to-vascular-wall SPP1 signaling increased in all three patient pairs. BCAP31 was also increased in paired plaque, rupture-macrophage, and intraplaque-hemorrhage cohorts and belonged to a plaque-associated coexpression module. In macrophages derived from THP-1 cells and treated with oxLDL, BCAP31 knockdown increased ER-stress transcripts, nuclear DDIT3, inflammatory cytokine expression and release, and Annexin V-positive apoptosis. The chemical chaperone 4-phenylbutyrate attenuated these effects.ConclusionHuman plaque transcriptomics and macrophage perturbation support a stress-adaptive role for BCAP31 in ER-stress-associated inflammation and apoptosis. Increased tissue expression and the adverse effects of depletion indicate that plaque-associated upregulation may reflect a compensatory response.
