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Reynolds Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014172","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008569","name":"Oklahoma Center for the Advancement of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008569","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Liver aging is characterized by chronic inflammation and metabolic dysfunction that drive progression of metabolic dysfunction\u2010associated steatotic liver disease (MASLD). Necroptosis, a pro\u2010inflammatory form of cell death via the Receptor\u2010Interacting serine\/threonine\u2010Protein Kinase 1 (RIPK1)\u2010RIPK3\u2010Mixed Lineage kinase domain Like pseudokinase (MLKL) pathway, is activated in aging livers, and systemic inhibition of this pathway reduces hepatic inflammation and pathology. The cell type\u2010specific role of necroptosis in liver aging, however, is unclear. Notably, RIPK3 is suppressed in hepatocytes under metabolic disease, suggesting necroptosis independent functions for MLKL. Here, we show that MLKL is elevated in aged hepatocytes and drives liver aging via a non\u2010necroptotic mechanism. Using hepatocyte\u2010specific MLKL\u2010overexpressing mice (MLKL\n                    <jats:sup>HepOE<\/jats:sup>\n                    ), we find that MLKL overexpression does not induce necroptosis but instead promotes cellular senescence, evidenced by increased p16INK4a and p21WAF1\/Cip1 and elevated senescence associated secretory phenotype (SASP). Mechanistically, MLKL induces hepatocyte mitochondrial dysfunction, with impaired respiration, altered mitochondrial dynamics, and increased reactive oxygen species, implicating oxidative stress as a contributing mechanism. This mitochondrial stress is associated with enhanced release of pro\u2010inflammatory extracellular vesicles (EVs) and induction of senescence in hepatocytes and non\u2010parenchymal cells. While hepatocytes contribute substantially to total senescent burden by abundance, macrophages emerge as a senescence\u2010enriched population, indicating amplification of senescence through non\u2010cell\u2010autonomous signaling. Collectively, these findings reveal a non\u2010lethal, non\u2010necroptotic function of hepatocyte MLKL in promoting liver inflammaging via mitochondrial dysfunction and paracrine senescence signaling, identifying MLKL as a regulator of hepatic aging and a potential therapeutic target in age\u2010associated liver disease.\n                  <\/jats:p>","DOI":"10.1111\/acel.70618","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:18:11Z","timestamp":1783135091000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Non\u2010Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver"],"prefix":"10.1111","volume":"25","author":[{"given":"Sabira","family":"Mohammed","sequence":"first","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Pennington","sequence":"additional","affiliation":[{"name":"Aging &amp; Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shylesh","family":"Bhaskaran","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Ohene\u2010Marfo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara F.","family":"Kneuper","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Georgescu","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamille","family":"Pitts","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Division of Digestive Diseases and Nutrition, Department of Medicine University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Tran","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongkai","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Oklahoma  Norman Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry The University of Oklahoma  Norman Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-7450","authenticated-orcid":false,"given":"Zhibo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Department of Chemistry and Biochemistry The University of Oklahoma  Norman Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiangang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Harold Hamm Diabetes Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Hannafon","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Department of Obstetrics and Gynecology University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Houchen","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"},{"name":"Division of Digestive Diseases and Nutrition, Department of Medicine University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Wren","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Yabluchanskiy","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery University of Oklahoma Health Campus  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Galvan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; 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