A STAT1/ETC/GBP1 axis represents a potential therapeutic target for noncommunicable granulomatous skin disease

作者：Manuel Huerta Arana, Henning Klapproth, Michal A. Stanczak, Luisa Bopp, Karla Witschurke, Robert Seitz, Maria Lopéz Martinez, Jan Zamek, Sinika Henschke, Nisha Rana, David O’Sullivan, Joy Steinkamp, Jan-Wilm Lackmann, William Damsky, Esther von Stebut, David E. Sanin, Paola Zigrino, Ramon I. Klein Geltink, Edward J. Pearce, Erika L. Pearce, Mario Fabri · 发表于：Science Advances · 年份：2026 · DOI：10.1126/sciadv.aea0773 · 研究领域：Sarcoidosis and Beryllium Toxicity Research、Skin Diseases and Diabetes、Metabolism, Diabetes, and Cancer

Granuloma annulare (GA) and cutaneous sarcoidosis (cSAR) have an overlapping immunopathology, in which the aberrant activation of macrophages by IFN-γ constitutes a central driver. Nevertheless, the molecular understanding in GA and cSAR macrophages remains limited. We reanalyzed single-cell RNA sequencing data of GA and cSAR and performed in vitro experiments with primary human cells showing that oxidative phosphorylation (OXPHOS) is a dominant metabolic pathway in IFN-γ-activated macrophages. Furthermore, we identify an IFN-γ-induced response network in GA and cSAR macrophages, sensitive to electron transport chain (ETC) inhibitors. Guanylate-binding protein 1 (GBP1) was central in controlling IFN-γ-mediated macrophage activation. Meanwhile, inhibition of IFN-γ signaling, ETC complexes, and GBP1 reduced granuloma formation in a human in vitro model. Metformin, a clinically used ETC complex I inhibitor, suppressed IFN-γ activation of macrophages and in vitro granulomas. Together, we suggest that OXPHOS and GBP1 represent druggable targets in granulomatous diseases and that drug repurposing of metformin is a possible strategy.