ArticleProceedings of the National Academy of Sciences of the United States of America2020
Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 83 citations in OpenAlex.
- Alcohol Consumption Is Associated with Poor Prognosis in Obese Patients with COVID-19: A Mendelian Randomization Study Using UK Biobank.Nutrients · 2021Trial
- Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers.Cell death and differentiation · 2026Article
- The cGAS-STING Pathway: A Double-Edged Regulator of Neuroinflammation and Myelin Regeneration.Molecular neurobiology · 2026Review
- Integrated Network and Transcriptomic Analyses Identify a Candidate Ethanol-ADAM17 Molecular Axis Associated with Glioblastoma Progression.International journal of molecular sciences · 2026Article
- GPAM mediates mitochondrial dysfunction and the progression of alcoholic liver disease through lipid remodeling.Science advances · 2026Article
- Non-transcriptional activity of IRF3 promotes liver fibrosis and stress granule assembly via a dsRNA-TLR3-dependent pathway in hepatic stellate cells.Hepatology (Baltimore, Md.) · 2026Article
- Targeting the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway: An Emerging Therapeutic Strategy for Digestive Diseases.Clinical and translational gastroenterology · 2026Review
- Cyclic GMP-AMP synthase deficiency predisposes the liver to alcohol-induced cell death and ER stress.Hepatology communications · 2026Article
- Interferon Regulatory Factors in Alcohol-Associated Liver Disease: Cell-Type Programs, Danger Signaling, and Therapeutic Opportunities.Current issues in molecular biology · 2026Review
- Iron-related intercellular communication in the liver: Main players and mechanisms.European journal of clinical investigation · 2026Review
- cGAS-STING signaling pathway as a therapeutic target in human diseases.Chinese medical journal · 2025Review
- Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies.Molecular and cellular biochemistry · 2025Review
- The Double-Edged Effect of Connexins and Pannexins of Glial Cells in Central and Peripheral Nervous System After Nerve Injury.Molecular neurobiology · 2025Review
- Phytochemicals Targeting Inflammatory Pathways in Alcohol-Induced Liver Disease: A Mechanistic Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeting cGAS-STING: modulating the immune landscape of hepatic diseases.Frontiers in immunology · 2025Review
- DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects.Immunological reviews · 2025Review
- The Role of Mitochondrial Quality Control in Liver Diseases: Dawn of a Therapeutic Era.International journal of biological sciences · 2025Review
- The role of cGAS-STING signaling in the liver and gastrointestinal system: from signaling networks to target intervention.Frontiers in immunology · 2025Review
- Gut‑liver axis in liver disease: From basic science to clinical treatment (Review).Molecular medicine reports · 2025Review
- Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
19 authors at 5 institutions in 1 country.
Funding
Abstract
Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.