SIRT3 inhibits fibroblast-like synoviocytes activation in rheumatoid arthritis through delactylation of H3K18

Abstract Objectives Metabolic reprogramming and epigenetic modifications are key contributors to the development of RA. Recent studies have identified lactate-dependent histone modifications as a novel epigenetic mechanism linking glycolysis to gene regulation. However, the precise role of histone lactylation in RA pathogenesis remains unclear. We aimed to elucidate the specific mechanism of histone lactylation, particularly H3K18la, in the pathogenesis of RA and to explore the therapeutic potential of the SIRT3-mediated delactylation process. Methods H3K18la levels in synovial tissue from RA patients were assessed using western blot and immunohistochemistry. CIA models combined with fibroblast-like synoviocytes (FLS) were used to explore H3K18la effects. CUT&Tag and RNA-sequencing identified pathways driven by H3K18la. SIRT3 function was validated using si-SIRT3 and the SIRT3 agonist honokiol in FLS. SIRT3 expression was assessed in peripheral blood mononuclear cells (PBMCs) from RA patients, and macrophage–FLS co-culture experiments evaluated SIRT3 knockdown effects. Results Lactylation, particularly H3K18la, was significantly elevated in the synovial tissue of RA patients. Reducing H3K18la alleviated CIA model–associated symptoms and mitigated the pathogenic effects of TNF-α on FLS, whereas increasing H3K18la exacerbated TNF-α–induced pathology. H3K18la and lactate co-regulated pathways included chemokine signalling and the inflammatory mediator of transient receptor potential channels. Furthermore, SIRT3, a key regulator of H3K18la, was downregulated in PBMCs from RA patients. Reduced SIRT3 increased H3K18la in FLS and macrophages, which activated FLS. Conclusions SIRT3 suppresses RA progression by delactylating H3K18. These findings may pave the way for novel lactylation-targeted therapies in RA.