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

Gan Wu, Chenglin Yang, Yuan Huang, Bin Liu, Haige Zhai, Zelin Cao, Siyue Lu, Jijian Ji, Xinyue Yin, Xianming Xin, Shengwei Jin (), Youzhi Cai () and Jianguang Wang ()
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Gan Wu: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Chenglin Yang: Zhejiang University
Yuan Huang: Wenzhou Medical University
Bin Liu: Wenzhou Medical University
Haige Zhai: Wenzhou Medical University
Zelin Cao: Wenzhou Medical University
Siyue Lu: Wenzhou Medical University
Jijian Ji: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Xinyue Yin: Wenzhou Medical University
Xianming Xin: Wenzhou Medical University
Shengwei Jin: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Youzhi Cai: Zhejiang University
Jianguang Wang: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Elevated lactate in the joint microenvironment of rheumatoid arthritis patients is crucial for disease progression, though the mechanism remains unclear. This study shows significantly increased global lactylation levels within fibroblast-like synoviocytes from RA patients compared to healthy controls, with lactylated proteins being enriched in histones. Furthermore, we find anti-lactylated histone autoantibodies present in RA patients that positively correlate with Disease Activity Score 28. Using CUT&Tag and RNA-seq, we identify NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation. Functional studies reveal that NFATc2 promotes migration of RA-FLSs. Additionally, using collagen antibody-induced arthritis and collagen-induced arthritis mouse models, we demonstrate that NFATc2 exacerbates RA disease progression through enhancing the cartilage invasive function of FLS. Here, we show that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactylated histone autoantibodies is promising as a diagnostic marker for RA.

Date: 2025
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DOI: 10.1038/s41467-025-64096-5

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