{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:05:32Z","timestamp":1784099132236,"version":"3.55.0"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"Office of Extramural Research","doi-asserted-by":"publisher","award":["R01CA256133, R01CA281285, 1R01DK141162"],"award-info":[{"award-number":["R01CA256133, R01CA281285, 1R01DK141162"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Mitochondrial DNA depletion syndromes (MDS) caused by deoxyguanosine kinase (DGUOK) deficiency are classically attributed to impaired mitochondrial DNA (mtDNA) maintenance. However, many patients develop hepatic steatosis and inflammation despite preserved mtDNA content, suggesting that additional pathogenic mechanisms contribute to disease. DGUOK is a key enzyme in the mitochondrial purine salvage pathway, but its role in coordinating purine metabolism with lipid homeostasis and innate immune signaling remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Acute DGUOK deficiency was induced in human hepatocellular carcinoma (HepG2) hepatocytes by siRNA-mediated knockdown. Mitochondrial integrity was assessed by mtDNA quantification, mitochondrial morphology, and oxidative phosphorylation (OXPHOS) protein expression. Lipid accumulation was evaluated by BODIPY staining, and transcriptomic changes were analyzed by bulk RNA sequencing. Purine imbalance was modeled by treatment of wild-type cells with 2\u2032-deoxyadenosine, followed by assessment of DNA methylation, interferon signaling, and lipid accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Acute DGUOK depletion induced a 2.9-fold increase in intracellular lipid droplet accumulation and activation of a type I interferon (IFN) transcriptional program despite preserved mtDNA copy number, mitochondrial morphology, and OXPHOS complex expression. Bulk RNA sequencing revealed induction of human endogenous retroviruses (HERVs) and interferon-stimulated genes (ISGs), together with suppression of lipid metabolic pathways and remodeling of purine-, methionine-, and methylation-associated networks. Consistent with these transcriptional changes, DGUOK-deficient cells exhibited an approximately 40% reduction in global DNA methylation, accompanied by hypomethylation of CpG-rich region within the\n                      <jats:italic>ISG15<\/jats:italic>\n                      and\n                      <jats:italic>ISG20<\/jats:italic>\n                      \u00a0promoters. Perturbation of purine homeostasis with exogenous 2\u2032-deoxyadenosine phenocopied DGUOK deficiency, driving DNA hypomethylation, activation of viral mimicry pathways, and lipid accumulation.a\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that acute DGUOK deficiency promotes innate immune activation and metabolic reprogramming through a purine-dependent mechanism that precedes mtDNA depletion and overt mitochondrial dysfunction. By linking disrupted mitochondrial purine salvage to HERV and ISG derepression, interferon signaling, epigenetic remodeling, and steatosis, this study provides a mechanistic framework for the immunometabolic pathology of DGUOK deficiency and identifies mitochondrial purine metabolism as an important regulator of hepatic immune and metabolic homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1758569","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:10:26Z","timestamp":1784095826000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes"],"prefix":"10.3389","volume":"17","author":[{"given":"Maija","family":"Corey","sequence":"first","affiliation":[{"name":"Center for Autoimmunity and Inflammation, La Jolla Institute for 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