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They consist of eight isozymes: TG1\u2013TG7 and factor XIIIa. Our previous studies have shown that TG1 and TG2 facilitate hepatic apoptosis, contributing to liver fibrosis, and that their crosslinking substrates\u2014cytokeratin 18 (K18) and cytokeratin 8 (K8)\u2014are also targeted by TGs in a bile\u2010duct\u2010ligation\u2010induced mouse model of liver fibrosis. However, the precise mechanisms by which TGs and keratins contribute to hepatocyte damage remain unclear. This study investigates the molecular mechanisms underlying TG1\u2010 and TG2\u2010mediated cell death in hepatocytes exposed to bile acids. HepG2 cells and primary hepatocytes were treated with glycochenodeoxycholic acid (GCDCA), a toxic bile salt elevated in cholestasis. GCDCA\u2010reduced cell viability and induced apoptosis in a dose\u2010dependent manner. Knockdown of K18\/K8 or TG1\/TG2 by siRNA significantly attenuated GCDCA\u2010induced apoptosis, indicating their contributory roles in hepatocyte injury. GCDCA\u2010treated cells showed increased levels of proteins crosslinked by TG1 and TG2.\n                    <jats:italic>In vivo<\/jats:italic>\n                    analysis using cholestatic model mice also showed elevated high\u2010molecular\u2010weight protein complexes involving K18\/K8, suggesting early\u2010stage Mallory body formation, as observed in chronic liver injury. Mass spectrometry identified cytoskeletal proteins, such as vimentin and periplakin, and regulatory proteins, such as ATP synthase subunit \u03b2 and PI3K adapter protein, as K18\u2010crosslinked partners. These results suggest that TG1\/TG2\u2010mediated aggregation of K18 sequesters essential structural and survival proteins, promoting hepatocyte apoptosis. Targeting these pathological interactions may provide a novel therapeutic strategy to mitigate liver fibrosis and improve hepatocyte survival.\n                  <\/jats:p>","DOI":"10.1111\/febs.70281","type":"journal-article","created":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T22:15:56Z","timestamp":1760307356000},"page":"1089-1105","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Transglutaminase\u2010mediated cytokeratin modifications implicated in bile\u2010acid\u2010induced hepatocyte death"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0059-9677","authenticated-orcid":false,"given":"Hideki","family":"Tatsukawa","sequence":"first","affiliation":[{"name":"Cellular Biochemistry Lab., Graduate School of Pharmaceutical Sciences Tokai National Higher Education and Research System, Nagoya University  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