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

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.