Multi-omics and causal inference reveal lactylation-based osteoblast regulatory networks and drug candidates

Bone loss-related disorders, driven by impaired osteoblast activity, pose a growing global health challenge, yet current anabolic therapies remain limited due to an incomplete understanding of osteoblast dysfunction. Emerging evidence suggests that lactate-derived lysine lactylation-a glycolysis-linked PTM-may regulate osteoblast differentiation and bone homeostasis, though its landscape and functional impact in osteoblasts are largely unknown. Here, we integrated multi-omics profiling, Mendelian randomization (MR), and computational modeling to investigate lactylation-mediated osteogenic regulation. Using in vitro osteoblast models, we mapped dynamic proteomic and lactylome changes during differentiation, identifying 43 key proteins with concurrent alterations in expression and lactylation. Integrated MR analysis of human genetic data identified NANS and SPTLC1 as causal regulators of bone mineral density. Molecular dynamics simulations revealed lactylation-driven functional remodeling of these proteins, and network pharmacology suggested FDA-approved compounds (e.g., Suramin sodium and Paritaprevir) as potential osteogenic agents. This study advances mechanistic understanding of osteogenesis and provides a framework for discovering small molecules that mimic lactylation-induced conformational changes for drug repurposing in clinical applications.