The role of lactylation modifications in musculoskeletal diseases: From mechanism to clinical application.

Lactylation, a recently discovered histone and non-histone modification driven by lactate, has redefined the understanding of how metabolic by-products regulate gene expression. Beyond its conventional role as an energy substrate, lactate emerges as a pivotal signaling mediator that couples cellular metabolism with epigenetic regulation. In musculoskeletal disorders, aberrant lactylation has been implicated in the disruption of osteogenic-osteoclastic balance, extracellular matrix homeostasis, and regenerative capacity, thereby linking cellular metabolic stress to pathological tissue remodeling. These findings position lactylation as a unifying mechanism across osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. Yet, the field remains in its infancy: the enzymatic machinery of lactylation is incompletely characterized, context-specific functions are poorly defined, and translation to human pathology is scarce. Conceptualizing lactylation as a metabolic-epigenetic nexus not only reframes our understanding of musculoskeletal biology but also highlights new opportunities for biomarker discovery and targeted epigenetic therapies. Addressing these challenges will be essential to harness the clinical potential of this emerging regulatory paradigm.