The role of lactate on arthritis-associated cells: physiology, pathology, and therapeutic strategies.

Lactate, as a terminal metabolite of glycolysis, is enriched in arthritis-associated cells and the inflammatory microenvironment, and it exhibits complex bidirectional regulatory features in the pathological processes of osteoarthritis (OA) and rheumatoid arthritis (RA). Physiologically, lactate is involved in cellular energy metabolism, is a key intermediate in gluconeogenesis, participates in a series of signaling pathways, and regulates epigenetic modifications through histone lactylation. In arthritic inflammation, elevated lactate concentrations affect the metabolism and function of intra-articular cells. Aging, a primary risk factor for OA, exacerbates this process by promoting mitochondrial dysfunction and a metabolic shift towards glycolysis, further amplifying lactate production. By regulating the metabolism and signaling pathways of chondrocytes, osteoblasts, osteoclasts, synovial fibroblasts, and immune cells, lactate is involved in the onset and progression of OA and RA. In OA, lactate accumulation leads to chondrocyte hypertrophy and senescence and increases bone burden, whereas in RA, lactate exacerbates the inflammatory response by inducing metabolic reprogramming of synovial cells and immune cells. The effect of lactate on macrophage polarization is two-sided, promoting both anti-inflammatory M2-type polarization and potentially enhancing pro-inflammatory responses. Targeting lactate metabolism or its associated signaling pathways may provide novel strategies for the treatment of arthritis. In the future, the cell-specific mechanism of lactate metabolism and the clinical translational pathways need to be explored in depth to provide new perspectives for the precision treatment of arthritis.