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bioRxiv · 10.64898/2026.05.08.723914

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.
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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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Geng, S., Tang, R.-C., Yu, H., Zhang, A., Yu, S.-S., Zhang, L., Zhang, J.. 2026-05-12. The gut microbiota metabolite Urolithin A mitigates JAK signaling to suppress cytokine-mediated autoimmune diseases. https://doi.org/10.64898/2026.05.08.723914

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