Mammalian STE20-like kinase 1 inhibits synoviocytes activation in rheumatoid arthritis through mitochondrial dysfunction mediated by SIRT3/mTOR axis

Abstract

Abstract Mammalian STE20-like kinase 1 (MST1) plays a pivotal role in the progression of cancer and autoimmune diseases by modulating cell proliferation, differentiation, and apoptosis, among other cellular processes. However, its role in rheumatoid arthritis (RA) and its downstream targets remain unclear. In the present study, our results show that MST1 expression is significantly downregulated in fibroblast-like synoviocytes (FLSs) from rheumatoid arthritis patients compared with FLSs from normal trauma controls. Furthermore, MST1 overexpression in RA-FLSs led to augmented apoptosis and a marked reduction in both cell migration and invasion. Mechanistically, upregulation of MST1 expression promotes mitochondrial fission, weakens mitochondrial fusion, curtails mitophagy, and inhibits NF-κB activation by constraining Sirtuin-3 (SIRT3). This cascade of events results in mitochondrial impairment and triggers the mitochondria-driven apoptosis pathway. This ultimately amplifies apoptosis, diminishes cell migration and invasion, and mitigates inflammation. Enhanced MST1 cleavage by the MST1 agonist, chelerythrine, alleviated joint synovial inflammation and bone and cartilage destruction and erosion in rats with adjuvant-induced arthritis (AIA). In summary, this study suggests that MST1 regulates the activation of RA-FLSs through the interplay of mitochondrial fission, fusion and mitophagy, laying a foundation for exploring new therapeutic targets for rheumatoid arthritis.