Investigating the Mechanistic Link Between Lactate-Induced Histone Lactylation and Cellular Senescence in Osteoarthritis Chondrocytes: Implications for Therapy

Chondrocyte senescence accelerates osteoarthritis (OA) progression, with dysregulated glycolysis potentially driving this process through lactate accumulation and histone lactylation. However, the mechanistic connection between lactate-induced lactylation and cellular senescence in OA chondrocytes remains poorly understood. This study elucidates this relationship and explores its therapeutic relevance. Using clinical OA cartilage, animal models, and IL-1β-stimulated chondrocytes, we demonstrated enhanced glycolysis and senescence activities. Increased glycolytic activity and lactate accumulation promoted cellular senescence in the OA microenvironment. Elevated lactate levels increased global lactylation, with H4K12la as the predominant mark. H4K12la-targeted CUT&TAG analysis identified TRIM29 as a key regulator. H4K12la promotes TRIM29 transcription, which activates the PI3K-AKT pathway via direct and EGFR-mediated mechanisms, leading to autophagy inhibition and senescence. Interventions such as SIRT1 overexpression or intra-articular oxamate injection reduced lactylation, inhibited glycolysis, and mitigated cartilage degeneration. These findings demonstrate that glycolytic lactate-induced H4K12la fosters senescence through TRIM29-mediated PI3K-AKT activation, highlighting the inhibition of glycolysis or lactylation as a promising therapeutic strategy for OA.