Lactate‐Driven Epigenetic Reprogramming of Osteogenesis: H3K18 Lactylation Activates m6A / YTHDF1 ‐Dependent YAP1 Signaling to Combat Bone Loss

ABSTRACT Postmenopausal osteoporosis is marked by progressive bone loss and deterioration of trabecular microarchitecture, largely driven by impaired osteogenic differentiation of bone marrow–derived mesenchymal stem cells (BMSCs). Using ovariectomized (OVX) mice and OVX‐derived BMSCs, this study systematically investigated the role of lactate and histone lactylation in bone metabolism. We found that lactate levels and histone H3 lysine 18 lactylation (H3K18la) were markedly reduced in OVX femoral tissues, accompanied by diminished osteogenic capacity of BMSCs. Integrated epigenomic and transcriptomic analyses identified the m6A reader YTHDF1 as a key downstream target associated with H3K18la. Mechanistic studies demonstrated that YTHDF1 enhances osteogenic differentiation by promoting m 6 A‐dependent translation of YAP1, as confirmed by RIP‐qPCR and dual‐luciferase reporter assays. Elevation of lactate levels increased H3K18la, upregulated the YTHDF1‐YAP1 axis, improved BMSC osteogenesis, and alleviated osteoporotic phenotypes in OVX mice. In addition, p300 was shown to regulate H3K18la levels and influence osteogenic differentiation in BMSCs. Collectively, this study identifies a previously unrecognized “lactate‐H3K18la‐YTHDF1‐YAP1” regulatory axis, linking metabolic status to epigenetic modification and translational control in osteoporosis, and provides new mechanistic insights and potential therapeutic targets for bone loss.