Lactate-driven lactylation reprograms chondrocyte fate and joint inflammation in osteoarthritis: linking metabolism...

The sustained progression of osteoarthritis (OA) arises not only from mechanical injury and inflammatory stimulation but also from the gradual loss of chondrocyte homeostatic identity. However, a unifying mechanism explaining how metabolic abnormalities within the joint microenvironment are converted into relatively stable degenerative programs remains lacking. The discovery of lactylation provides a new perspective on this question. OA-associated hypoxia, inflammation, and aberrant mechanical loading can promote glycolytic reprogramming and lactate accumulation, while lactate further channels metabolic stress into chromatin regulation and protein functional networks through histone and non-histone lactylation. Current evidence suggests that this process does not merely amplify a single catabolic pathway, but reshapes chondrocyte fate at multiple levels by impairing matrix-maintaining capacity, driving the transition from a homeostatic phenotype toward catabolic, fibrotic, and senescent states, and altering cellular susceptibility to oxidative injury and pathological cell death. Meanwhile, metabolic reprogramming in synovial cells and immune cells may expand the intra-articular lactate pool, thereby linking intracellular lactylation changes with inter-tissue inflammatory crosstalk. Notably, the effects of lactylation are not uniformly pathogenic, but depend on the modified site, protein substrate, cellular state, redox environment, and disease stage. This bidirectionality is evident in both histone and non-histone lactylation: UGDH K6 lactylation and selected H3K18la-associated programs are linked to matrix damage and fibrotic phenotypes, whereas H3K56la may preserve COL2A1 expression and enhance chondrocyte stress adaptation under specific post-traumatic and redox conditions. Lactylation is therefore better understood as a metabolic state-driven "fate code" rather than a passive marker of lactate accumulation. This review integrates the continuum linking lactate metabolism, site-specific lactylation, and chondrocyte fate remodeling, with particular emphasis on matrix homeostasis, cellular senescence, survival-death transitions, and the inflammatory microenvironment. It also discusses the therapeutic implications of shifting from global modulation of lactylation toward cell- and site-specific intervention. This framework may deepen our understanding of OA chronicity and provide a theoretical basis for metabolic phenotype stratification and disease-modifying therapy.