Neutrophil extracellular traps in rheumatoid arthritis: Activating fibroblast-like synoviocytes via ATP citrate lyase.

Synovial hyperplasia and inflammation are the main pathological features of rheumatoid arthritis (RA). Fibroblast‑like synoviocytes (FLSs) are the major effector cells contributing to chronic inflation and joint injury in the synovial microenvironment. Neutrophil extracellular traps (NETs) play an important role in the pathogenesis of RA, but their downstream regulatory mechanisms remain unclear. In order to improve the therapeutic prospects for RA, it is crucial to identify the targets of NETs and the molecular mechanisms of synovial dysfunction. ATP-citrate lyase (ACLY) directs glucose metabolism to de novo lipogenesis (DNL) by generating acetyl-CoA, which is also an acetyl donator to protein acetylation. ACLY has gained attention in studies on tumors, fatty liver, inflammation, and metabolic diseases. However, its involvement in RA progression is still uncertain. The present study revealed increased expression of NETs in the RA synovial microenvironment, including synovial fluid and synovial tissue, and a positive correlation to disease activity. In vitro experiments demonstrated that NETs activate ACLY, which not only triggers DNL, and enhances procreation, migration and invasiveness of RA-FLSs, but also stimulates the nuclear factor kappa-B (NF-κB) signaling pathway. This enhances the expression and nuclear translocation of acetyl-NF-kappaB p65 (Ac-p65), intensifying the transcription of inflammatory mediators and exacerbating synovial inflammation. Additionally, a high level of NETs expression in synovial tissues of arthritis animal models and the therapeutic effect of inhibiting ACLY on joint inflammation, bone erosion and bone destruction were also confirmed in vivo. In conclusion, our results elucidate the molecular mechanisms involved in the activation of RA-FLSs by NETs, and ACLY may be a candidate target for regulating metabolic reprogramming and inflammation to mitigate RA joint injuries.