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.
Authors
- Manuel Huerta Arana
- Robert Seitz
- Mario Fabri (ORCID: https://orcid.org/0000-0002-9586-2230)
- Joy Steinkamp (ORCID: https://orcid.org/0000-0001-9842-3818)
- Sinika Henschke (ORCID: https://orcid.org/0000-0002-4264-1581)
- David O’Sullivan (ORCID: https://orcid.org/0000-0001-5151-8924)
- Maria Lopéz Martinez
- David E. Sanin (ORCID: https://orcid.org/0000-0003-0188-7267)
- Luisa Bopp (ORCID: https://orcid.org/0000-0002-9089-5228)
- Erika L. Pearce (ORCID: https://orcid.org/0000-0001-5592-5439)
- Esther von Stebut (ORCID: https://orcid.org/0000-0001-9802-9642)
- Ramon I. Klein Geltink
- Henning Klapproth (ORCID: https://orcid.org/0000-0003-1966-3069)
- Nisha Rana (ORCID: https://orcid.org/0000-0001-9896-8674)
- Paola Zigrino (ORCID: https://orcid.org/0000-0002-7470-0064)
- Jan Zamek (ORCID: https://orcid.org/0000-0002-8197-0003)
- William Damsky
- Karla Witschurke
- Michal A. Stanczak (ORCID: https://orcid.org/0000-0003-2563-7254)
- Edward J. Pearce (ORCID: https://orcid.org/0000-0003-1001-9656)
- Jan-Wilm Lackmann (ORCID: https://orcid.org/0000-0001-8182-8034)
Institutions
- Bloomberg (United States) (US)
- University of British Columbia (CA)
- Johns Hopkins University (US)
- University of Cologne (DE)
- Malaghan Institute of Medical Research (NZ)
- University Hospital Regensburg (DE)
- Yale University (US)
- Sidney Kimmel Cancer Center (US)
- Max Planck Institute for Metabolism Research (DE)
- Jena University Hospital (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- BC Children's Hospital (CA)
- University Hospital Cologne (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-29
- DOI
- https://doi.org/10.1126/sciadv.aea0773
- Primary Topic
- Sarcoidosis and Beryllium Toxicity Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Center for Molecular Medicine Cologne, University of Cologne