{ "abstract": "Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor-mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas-/- mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.", "abstract_shown": true, "affiliations": [ "Lineberger Comprehensive Cancer Center", "Department of Biochemistry and Biophysics", "Bioinformatics and Analytics Research Collaborative (BARC)", "Carolina Institute for Developmental Disabilities", "University of North Carolina (UNC) Neuroscience Center, and", "Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.", "Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, North Carolina, USA.", "Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.", "Department of Data Science, Dana-Farber Cancer Institute Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.", "Marsico Lung Institute/UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.", "Department of Medicinal Chemistry, School of Pharmacy", "Philips Institute for Oral and Craniofacial Molecular Biology, School of Dentistry; and", "Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.", "Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.", "Department of Biology", "UNC Proteomics Core Facility, Department of Pharmacology", "Thurston Arthritis Research Center; and", "Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA." ], "article_type": "research article", "arxiv": null, "author_total": 28, "authors": [ { "affs": [ 0, 1 ], "name": "Yu Deng" }, { "affs": [ 2 ], "name": "Matthew J. Niederhuber" }, { "affs": [ 0, 1 ], "name": "Zhichuan Zhu" }, { "affs": [ 0, 2, 3, 4, 5 ], "name": "Austin J. Hepperla" }, { "affs": [ 0, 1 ], "name": "Le Yu" }, { "affs": [ 1 ], "name": "Quentin Hahn" }, { "affs": [ 6 ], "name": "Joshua Hartsell" }, { "affs": [ 7 ], "name": "Tooba Rashid" }, { "affs": [ 0, 5 ], "name": "Piotr A. Mieczkowski" }, { "affs": [ 5 ], "name": "Hemant Kelkar" }, { "affs": [ 0, 3, 4, 5, 8 ], "name": "Jeremy M. Simon", "orcid": "0000-0003-3906-1663" }, { "affs": [ 0, 1 ], "name": "Yanqiong Zhang" }, { "affs": [ 9 ], "name": "Alessandra Livraghi-Butrico", "orcid": "0000-0001-8751-3631" }, { "affs": [ 9 ], "name": "Meredith J. Zeller" }, { "affs": [ 9 ], "name": "Joseph G.C. Kennedy" }, { "affs": [ 9 ], "name": "Jazmin F. DePriest" }, { "affs": [ 10, 11, 12 ], "name": "Jiong Li" }, { "affs": [ 10, 12 ], "name": "Yan Zhang" }, { "affs": [ 13 ], "name": "Xing Qiu" }, { "affs": [ 13 ], "name": "H. Ümit Kaniskan" }, { "affs": [ 13 ], "name": "Jian Jin", "orcid": "0000-0002-2387-3862" }, { "affs": [ 5, 14 ], "name": "Corbin D. Jones" }, { "affs": [ 15 ], "name": "Laura E. Herring", "orcid": "0000-0003-4496-7312" }, { "affs": [ 0, 5, 7, 16, 17 ], "name": "Douglas H. Phanstiel" }, { "affs": [ 6 ], "name": "Xiaojing Liu" }, { "affs": [ 0, 5 ], "name": "Jesse R. Raab" }, { "affs": [ 0, 1 ], "name": "Brian D. Strahl", "orcid": "0000-0002-4947-6259" }, { "affs": [ 0, 1 ], "name": "Pengda Liu" } ], "bibtex": "https://research.draconitic.com/paper/76wqj1vmdryty.bib", "cited_by": 0, "doi": "10.1172/jci205579", "fulltext_url": "https://europepmc.org/articles/PMC13722394", "id": "76wqj1vmdryty", "issns": [ "0021-9738", "1558-8238" ], "landing_url": "https://europepmc.org/article/MED/42969224", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Research Article" ], [ "openalex", "1306|Cancer, Lipids, and Metabolism" ] ], "openalex": "W7225045232", "pdf_url": "https://europepmc.org/articles/PMC13722394?pdf=render", "pmcid": "PMC13722394", "pmid": "42969224", "published": "2026-11-02", "publisher": "American Society for Clinical Investigation", "ris": "https://research.draconitic.com/paper/76wqj1vmdryty.ris", "sources": [ { "first_seen": "2026-11-03T15:20:53Z", "native_id": "MED:42969224", "source": "europepmc", "url": "https://europepmc.org/article/MED/42969224" }, { "first_seen": "2026-11-04T12:22:00Z", "native_id": "PMC13722394", "source": "pmc", "url": "https://doi.org/10.1172/jci205579" } ], "subjects": [ { "field": "medicine", "origin": "openalex:1306|Cancer, Lipids, and Metabolism", "subfield": "oncology" } ], "title": "Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.", "title_text": "Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.", "type": "peer-reviewed", "updated_at": "2026-11-05T12:20:12Z", "url": "https://research.draconitic.com/paper/76wqj1vmdryty", "venue": "The Journal of clinical investigation", "versions": [] }