Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.

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Publication Details

Journal
Nature Communications
Published
2026-03-03
DOI
https://doi.org/10.1038/s41467-026-69979-9
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

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article

Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome

Surabhi Jagtap, Jacqueline Leib, Víctor Paredes, Tinhinane Fali et al.
Nature Communications
interferon and immune responses
article

Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome

Surabhi Jagtap, Jacqueline Leib, Víctor Paredes, Tinhinane Fali, Ivan Nemazanyy, M Zarhrate, Brieuc P. Pérot, B. Neven, Camille de Cevins, Pierre Marie Quartier, Marine Luka, F. Carbone, Alice Lepelley, Brigitte Bader-Meunier, Alain Fischer, Alexandre Belot, Marie-Louise Frémond, Mickaël M. Ménager, Alexandre Pierga, Maxime Batignes
article en

Abstract

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.

Nature Communications
Université Claude Bernard Lyon 1 (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Collège de France (FR), Université Paris Cité (FR), Sorbonne Université (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Institut d'Etudes Avancées Paris (FR), Pitié-Salpêtrière Hospital (FR), Institut des Maladies Métaboliques et Cardiovasculaires (FR), Centre International de Recherche en Infectiologie (FR), Institut des Maladies Génétiques Imagine (FR)
Sanofi, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Régional Universitaire de Montpellier, Fondation Bettencourt Schueller, Assistance publique-Hôpitaux de Paris
Good health and well-being
Openalex Percentile: Top 35%
interferon and immune responses
DOIOpen Access PDFOpenAlex
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