Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds

Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease characterized by persistent inflammation and hyperplasia of the synovial membrane, the degradation of cartilage, and the erosion of bones in diarthrodial joints. The inflamed joints of patients with RA have been recognized to be a site of hypoxic microenvironment which results in an imbalance of lactate metabolism and the accumulation of lactate. Lactate is no longer considered solely a metabolic waste product of glycolysis, but also a combustion aid in the progression of RA from the early stages of inflammation to the late stages of bone destruction.To review the pathogenic mechanisms of lactate metabolism in RA and investigate the potential of natural compounds for treating RA linked to the regulation of imbalance in lactate metabolism.Research advances in our understanding of lactate metabolism in the pathogenesis of RA and novel pharmacological approaches of natural compounds by targeting lactate metabolic signaling were comprehensively reviewed and deeply discussed.Lactate produced by RA synovial fibroblasts (RASFs) acts on targeted cells such as T cells, macrophages, dendritic cells and osteoclasts, and affects their differentiation, activation and function to accelerate the development of RA. Many natural compounds show therapeutic potential for RA by regulating glycolytic rate-limiting enzymes to limit lactate production, and affecting monocarboxylate transporter and acetyl-CoA carboxylase to inhibit lactate transport and conversion.Regulation of imbalance in lactate metabolism offers novel therapeutic approaches for RA, and natural compounds capable of targeting lactate metabolic signaling constitute potential candidates for development of drugs RA.