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The gut microbiota metabolite Urolithin A mitigates JAK signaling to suppress cytokine-mediated autoimmune diseases

Geng, S.; Tang, R.-C.; Yu, H.; Zhang, A.; Yu, S.-S.; Zhang, L.; Zhang, J.

2026-05-12 immunology
10.64898/2026.05.08.723914 bioRxiv
Show abstract

Aberrant activation of type I interferon (IFN-I) is closely related to the development of autoimmune diseases. The metabolic regulation of cytokine signaling is essential for immune homeostasis. In this study, we characterized Urolithin A(UA), a natural gut-derived metabolite, as an inhibitor of Janus kinase (JAK) signaling. UA was found to broadly dampen JAK phosphorylation and the downstream signaling induced by cytokines such as type I interferons (IFN-I), type II interferons (IFN-II), and interleukin-6 (IL-6). UA can directly bind to JAK1 JH1 domain and treatment with UA attenuated autoimmune pathogenesis in Trex1-KO mice, IMQ-induced SLE and psoriasis models. Our findings unveil that UA is an anti-inflammatory metabolite that promotes immune homeostasis and could be used to treat inflammatory and autoimmune diseases.

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