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The role of mitochondrial dynamics in liver disease and cancer remains poorly understood. We analyzed single, double, and triple liver-specific KO mice lacking mitochondrial fission and fusion proteins using systematic analyses of mitochondrial morphology, untargeted metabolomics, RNA-seq, hydrodynamic tail vein injection of oncogenes, and human hepatocellular carcinoma samples. Liver-specific\n                    <jats:italic>Dnm1l-<\/jats:italic>\n                    KO (L\n                    <jats:italic>-Dnm1l<\/jats:italic>\n                    \u2013KO) mice showed increased alanine aminotransferase levels and hepatic fibrosis, with spontaneous liver tumors developing by 12 to 18 months of age. L-\n                    <jats:italic>Mfn1<\/jats:italic>\n                    \u2013 and L-\n                    <jats:italic>Mfn2<\/jats:italic>\n                    \u2013KO mice showed no significant liver damage or tumor development, although a small percentage of L-\n                    <jats:italic>Mfn1<\/jats:italic>\n                    ,\n                    <jats:italic>Mfn2<\/jats:italic>\n                    double KO mice developed tumors.\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    ,\n                    <jats:italic>Mfn1<\/jats:italic>\n                    , and\n                    <jats:italic>Mfn2<\/jats:italic>\n                    triple KO (TKO) mice experienced significantly reduced liver injury and fibrosis, along with decreased spontaneous and oncogene-induced tumorigenesis. L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    \u2013KO mice showed increased activation of the cGAS\/STING\/interferon pathway and pyrimidine metabolism, which were significantly normalized in TKO mice. Deletion of hepatic\n                    <jats:italic>cGas<\/jats:italic>\n                    reduced both basal and oncogene-induced liver injury and tumor development in L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    \u2013KO mice. These findings indicate that mitochondrial dynamics are crucial for maintaining hepatic pyrimidine metabolism and regulating the cGAS\/STING-mediated immune response to prevent liver tumorigenesis.\n                  <\/jats:p>","DOI":"10.1172\/jci194441","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T17:00:32Z","timestamp":1765904432000},"source":"Crossref","is-referenced-by-count":5,"title":["Genetic disruption of mitochondrial dynamics and stasis leads to liver injury and tumorigenesis"],"prefix":"10.1172","volume":"136","author":[{"given":"Xiaowen","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical 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