A STAT1/ETC/GBP1 axis represents a potential therapeutic target for noncommunicable granulomatous skin disease
- 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
2026-05-29
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.