Nitazoxanide alleviates collagen-induced arthritis by inhibiting STAT3-dependent Th17 cell differentiation and inflammatory cytokines production

Abstract

Nitazoxanide (NTZ), an FDA-approved anti-parasitic drug, has shown anti-inflammatory effects in rheumatoid arthritis (RA) fibroblast-like synoviocytes, yet its impact on immune cell function and its potential synergy with methotrexate (MTX) remains unclear. In this study, using a murine collagen-induced arthritis (CIA) model, we demonstrated that NTZ synergizes with MTX to delay arthritis onset and ameliorate joint pathology, accompanied by reduced inflammatory cell infiltration, synovial pannus formation, and bone destruction. Moreover, NTZ significantly suppressed inflammatory cytokine production in both murine splenocytes and human peripheral blood mononuclear cells from healthy donors and RA patients. In vivo findings from the CIA model further demonstrated that NTZ suppressed synovial IL-6 and pSTAT3 expression, as well as Th17 cell differentiation. And these effects collectively contributed to the improvement in arthritis score. Mechanistically, NTZ markedly inhibited the STAT3 signaling pathway in immune cells upon IL-6 or anti-CD3 stimulation. Additionally, it potently suppressed osteoclast differentiation of monocytes derived from RA patients. Taken together, this study provides a proof-of-concept for NTZ’s immunomodulatory activity in RA, yet the data remain insufficient for therapeutic claims and only lay the groundwork for further studies.