Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies

The elevated lactate in the joint microenvironment of patients with rheumatoid arthritis (RA) is crucial for disease progression, although the underlying mechanism remains to be elucidated. In this study, we observed significantly increased global lactylation levels within fibroblast-like synoviocytes (FLS) of RA patients compared to HC (healthy controls), and lactylated proteins were enriched in histones. Furthermore, we found that anti-lactated histone antibodies were detected in almost RA patients and positively correlated with Disease Activity Score 28 (DAS28). Then we identified NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation (H3K9la) using CUT&Tag combined with RNA-seq. Functional studies revealed that NFATc2 promotes migration of RA-FLSs. Additionally, using server combined immune-deficiency (SCID) and collagen-induced arthritis (CIA) mouse models, we demonstrated that NFATc2 exacerbates RA disease progression through enhanced FLS cartilage invasion function. Collectively, our findings suggest that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactated histone autoantibodies is promising as a diagnostic marker for RA.