Osteoclast-derived exosomal miR-378a-3p targets FTO-mediated m6A modification to promote osteogenesis and inhibit osteocyte apoptosis in alcohol-induced osteonecrosis of the femoral head

Background Alcohol-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 m 6 A pathway in AIONFH. Methods Rat 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 m 6 A levels were evaluated under ethanol exposure. An AIONFH rat model was used to assess the therapeutic effects of these exosomes in vivo . Results Ethanol 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, m 6 A levels decreased, osteogenic differentiation was inhibited, and apoptosis was increased. miR-378a-3p-enriched exosomes reversed these changes by reducing FTO expression, increasing m 6 A 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. Conclusion Osteoclast-derived exosomal miR-378a-3p protects against alcohol-induced bone damage by targeting FTO and regulating m 6 A modification. The miR-378a-3p/FTO/m 6 A pathway may be a potential therapeutic target for AIONFH.