Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes

15 Jul 20264 min read0 viewsJournal Feed

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IntroductionMitochondrial 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.
Methods. 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′-deoxyadenosine, followed by assessment of DNA methylation, interferon signaling, and lipid accumulation. Results.
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.

Frontiers in Immunology published a clinical update in Infectious Disease on 15 Jul 2026.

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Frontiers in Immunology