The novel biguanide SD282 suppresses autoimmune rheumatoid arthritis by controlling the Th17/Treg balance and restoring mitochondrial homeostasis via STAT3 regulation.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by dysregulated Th17 cell responses and osteoclastogenesis. While metformin has shown potential in autoimmune modulation, its efficacy is often limited by high dosage requirements. In this study, we evaluated the therapeutic efficacy and underlying molecular mechanisms of SD282, a newly synthesized biguanide derivative, in treating RA.

METHODS: The anti-arthritic effects of SD282 were assessed using a collagen-induced arthritis (CIA) mouse model. Murine and human immune cells were used to investigate the impact of SD282 on Th17/Treg differentiation, STAT3 signaling, mitochondrial respiration (OCR), and osteoclastogenesis.

RESULTS: SD282 treatment significantly ameliorated the clinical severity of CIA, reducing joint inflammation, cartilage damage, and bone erosion. At the cellular level, SD282 effectively inhibited Th17 differentiation and IL-17 production while promoting Foxp3 + Treg cells, thereby restoring immune homeostasis. Mechanistically, SD282 blocked STAT3 phosphorylation and normalized mitochondrial metabolic activity by enhancing OXPHOS complex potential. Furthermore, SD282 suppressed osteoclast differentiation by downregulating RANKL, MMP9, and NFATC1 signaling pathways.

CONCLUSION: Our findings demonstrate that SD282 acts as a potent multi-target agent that suppresses RA progression by synergistically regulating the STAT3-Th17-Mitochondria axis and bone metabolism. SD282 represents a promising pharmacological candidate for the treatment of autoimmune arthritis with a superior mechanistic profile compared to conventional biguanides.