Lactylation Dynamics and Its Regulatory Roles in Orthopedic Pathologies: A Research Update.

Post-translational modifications (PTMs) dynamically regulate cellular processes by modifying protein function. Among these, lactylation, a modification derived from lactate, functions through direct or indirect modification of histones or nonhistone proteins. While glycosylation and phosphorylation have established roles in bone metabolism and joint disorders, the biological significance of lactylation in musculoskeletal diseases remains underexplored. This study synthesizes current evidence investigating lactylation in four major orthopedic diseases: intervertebral disc degeneration (IVDD), osteoporosis (OP), osteoarthritis (OA), and spinal cord injury (SCI). The evidence indicates that lactylation modulates disease progression through dual mechanisms: coordinating cellular metabolism with extracellular matrix remodeling in IVDD and OA and regulating neuroimmune responses during SCI recovery. Notably, lactylation's regulatory patterns differ from classical PTMs by serving as a molecular bridge linking metabolic reprogramming to pathological tissue remodeling. This contrasts with phosphorylation, which primarily dominates signal transduction pathways. These insights reposition lactate from a metabolic byproduct to a disease-modifying signaling molecule, suggesting lactylation could inform therapeutic strategies for inflammatory, degenerative, and regenerative musculoskeletal disorders.