HDAC1-mediated PKM2 delactylation modification regulates CIRP-induced angiogenesis in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, inflammatory cell infiltration, and pathological angiogenesis, ultimately leading to progressive joint damage. Cold-inducible RNA-binding protein (CIRP) has been implicated in inflammatory responses; however, its role in RA-associated angiogenesis remains unclear. In this study, we demonstrate that CIRP gene knockout or pharmacological inhibition using C23 significantly attenuates arthritis severity and reduces synovial angiogenesis in adjuvant-induced arthritis models. In vitro experiments revealed that CIRP promotes human umbilical vein endothelial cell (HUVEC) tube formation, migration, and invasion by upregulating the expression of C-X-C motif chemokine receptor 4 (CXCR4) and Delta-like ligand 4 (DLL4). Notably, blocking extracellular CIRP with C23 inhibited CIRP-induced angiogenesis in HUVECs. Further investigations showed that Toll-like receptor 4 (TLR4) knockdown suppressed CIRP-induced angiogenesis in HUVECs, indicating that CIRP promotes angiogenesis through a TLR4-dependent mechanism. Subsequent mechanistic studies revealed that CIRP upregulates histone deacetylase 1 (HDAC1) expression via TLR4 in HUVECs. We therefore investigated the role of HDAC1 in CIRP-induced angiogenesis, and found that HDAC1 knockdown significantly inhibited this process. Moreover, CIRP promotes pyruvate kinase M2 (PKM2) nuclear translocation and suppresses PKM2 lactylation through the TLR4-mediated HDAC1 pathway. Furthermore, The PKM2 lysine 62 to arginine (K62R) mutant enhances PKM2 nuclear translocation and promotes angiogenesis. Taken together, these results suggest that HDAC1-mediated PKM2 delactylation modification regulates CIRP-induced angiogenesis in RA.