Journal Article

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

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

2026

Overview

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. Aicardi-Goutières syndrome (AGS) is a brain condition characterized by type I interferon (IFN)-mediated inflammation. Here, the authors demonstrate a negative correlation between the metabolic regulator, HIF-1α, and type-I IFN responses in AGS.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/1 / 38/109 / 38/91 / 631/80/304 / 692/699/249 / 82/58 / Acids / Adenosine / Autoimmune Diseases of the Nervous System - drug therapy / Autoimmune Diseases of the Nervous System - genetics / Autoimmune Diseases of the Nervous System - metabolism / Blood / Chemokine CXCL10 - metabolism / Children / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - metabolism / Disease / Double-stranded RNA / Female / Gene expression / Genes / Glutathione / Glycolysis / Glycolysis - drug effects / Glycolysis - genetics / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia-inducible factor 1 / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Inflammation / Interferon / Interferon Type I - metabolism / IP-10 protein / Leukocytes (mononuclear) / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - metabolism / Life Sciences / Lymphocytes / Machine learning / Metabolomics / Mitochondria - drug effects / Mitochondria - metabolism / Monocytes / multidisciplinary / Mutation / Nervous System Malformations - drug therapy / Nervous System Malformations - genetics / Nervous System Malformations - metabolism / Oxidative metabolism / Oxidative phosphorylation / Oxidative Phosphorylation - drug effects / Peripheral blood mononuclear cells / Phosphorylation / Proteins / SAM Domain and HD Domain-Containing Protein 1 - genetics / Science / Science (multidisciplinary) / Stabilization / Transcriptomics