Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease marked by persistent synovitis, whose pathogenic mechanisms are not fully understood. Neutrophil extracellular traps (NETs) are increasingly recognized as key drivers of synovial inflammation and tissue injury in RA. Emerging evidence suggests that metabolic reprogramming and epigenetic remodeling—particularly histone lactylation—are interconnected and may cooperatively promote inflammatory progression. Establishment of cohesion 1 homolog 2 (ESCO2), a member of the acetyltransferase family, has been implicated as a potential regulator linking metabolic cues to epigenetic modification. This study aims to elucidate the role and mechanism of ESCO2-dependent histone lactylation in NETs-induced activation of RA synovial fibroblasts (FLS).

Objectives: To examine ESCO2 expression in RA synovial tissues and FLS and assess its correlation with clinical indicators; To determine whether NETs upregulate ESCO2, thereby enhancing lactate production and histone H3 lysine 18 lactylation (H3K18la) in FLS; To characterize the functional consequences of the NETs–ESCO2–H3K18la axis on RA-FLS activation, including migration, invasion, proliferation, and pro-inflammatory mediator secretion, and to explore its therapeutic relevance.

Methods: Synovial tissues and synovial fluid were collected from RA patients and control subjects. ESCO2 expression was evaluated by Western blot and ELISA and correlated with clinical parameters. Neutrophils were isolated for NETs generation. RA-FLS were stimulated with NETs in vitro, followed by measurement of lactate levels and H3K18la. ESCO2 was silenced using siRNA to assess its role in NETs-induced lactylation and FLS activation. Functional assays included Transwell migration/invasion, wound healing, CCK-8 proliferation, and RT–qPCR analysis of inflammatory genes.

Results: ESCO2 expression was significantly increased in RA synovial tissues and synovial fluid. NETs stimulation upregulated ESCO2 in RA-FLS, elevated lactate production and H3K18la levels, and enhanced FLS migration, invasion, proliferation, and inflammatory gene expression. ESCO2 knockdown attenuated NETs-induced H3K18la and reduced FLS activation, indicating that ESCO2 is essential for the NETs-driven lactylation and pro-inflammatory phenotype of FLS.

Conclusions: Our findings suggest that NETs promote RA-FLS activation through upregulation of ESCO2, leading to lactate accumulation and H3K18 lactylation, which collectively sustain a pro-inflammatory synovial microenvironment. ESCO2-dependent histone lactylation represents a novel mechanism linking NETs to RA pathogenesis and highlights the metabolic–epigenetic axis as a potential therapeutic target in RA.

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Acknowledgments: NIL.

Disclosure of Interests: None declared.