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. RNA-seq profiling of fibroblast-like synoviocytes (FLS) from RA patients and healthy controls

类风湿关节炎（rheumatoid arthritis, RA）患者关节微环境中升高的乳酸水平对疾病进展至关重要，但其潜在调控机制仍有待阐明。本研究中，我们观察到RA患者的成纤维样滑膜细胞（fibroblast-like synoviocytes, FLS）内整体乳酸化水平显著高于健康对照（healthy controls, HC），且经乳酸化修饰的蛋白在组蛋白中富集。进一步研究发现，几乎所有RA患者体内均可检测到抗乳酸化组蛋白抗体，且该抗体水平与28项疾病活动度评分（Disease Activity Score 28, DAS28）呈正相关。我们结合CUT&Tag技术与RNA测序（RNA-seq），鉴定出核因子活化T细胞胞质因子2（NFATc2）是受组蛋白H3赖氨酸9乳酸化（H3K9la）调控的关键靶基因。功能实验结果显示，NFATc2可促进RA-FLS的迁移能力。此外，通过联合使用严重联合免疫缺陷（severe combined immune-deficiency, SCID）小鼠模型与胶原诱导性关节炎（collagen-induced arthritis, CIA）模型，我们证实NFATc2可通过增强FLS的软骨侵袭功能加重RA疾病进展。综上，本研究结果表明：经乳酸依赖性组蛋白乳酸化上调的靶基因NFATc2可作为潜在的干预治疗靶点，而抗乳酸化组蛋白自身抗体有望成为RA的诊断标志物。本数据集涵盖类风湿关节炎患者与健康对照的成纤维样滑膜细胞RNA测序转录组谱。