Pyruvate kinase M2 (PKM2) regulates rheumatoid arthritis by mediating glycolysis reprogramming through the Akt/mTOR pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Fibroblast-like synovial cells (FLSs) are the main effector cells in the synovial microenvironment that cause chronic swelling and joint injury, and their enhanced glycolytic metabolism can lead to persistent joint injury. As a key regulatory enzyme in glycolysis, pyruvate kinase M2 (PKM2) plays a crucial role in the pathogenesis of RA. However, the exact mechanism by which PKM2 induces the inflammatory response of RA-FLSs through enhanced glucose metabolism and its impact on the pathogenic behaviour of cells remain unclear. This study detected the expression of PKM2 in synovial tissues and RA-FLSs of patients with RA and explored the effect of PKM2 on collagen-induced arthritis (CIA) rats. The results showed that PKM2 was upregulated in the synovial tissue of RA and RA-FLSs. PKM2 could promote glucose uptake, ATP and lactic acid production, and extracellular acidification rate in RA-FLSs, thereby promoting the release of pro-inflammatory cytokines such as TNF-α, interleukin-1 β (IL-1β), and IL-6. However, inhibiting PKM2 can reverse these changes. In in vivo experiments, inhibition of PKM2 could significantly improve the clinical arthritis symptoms of CIA rats (reduce plantar swelling and arthritis score), down-regulate the expression of pro-inflammatory cytokines, and inhibit bone erosion in CIA rats, reducing inflammatory cell infiltration, synovial hyperplasia and joint destruction. Furthermore, inhibiting PKM2 can suppress the phosphorylated expression of Akt and mTOR proteins, thereby inhibiting glycolytic reprogramming. Our research results indicate that PKM2 mediates glycolytic reprogramming to induce the release of RA-FLSs inflammatory cytokines by activating the Akt/mTOR signaling pathway, thereby promoting the progression of RA. Therefore, PKM2 may be a candidate target for the treatment of RA. Targeting PKM2 to regulate glycolytic reprogramming can provide a new idea for the treatment of RA.