{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:48:29Z","timestamp":1781898509439,"version":"3.54.5"},"reference-count":68,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001056","name":"Gallipoli Medical Research Foundation","doi-asserted-by":"publisher","award":["Gallipoli Medical Research Foundation"],"award-info":[{"award-number":["Gallipoli Medical Research Foundation"]}],"id":[{"id":"10.13039\/501100001056","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Steatosis in donor livers poses a major risk of organ dysfunction due to their susceptibility to ischaemia-reperfusion (I\/R) injury during transplant. Necroptosis, a novel form of programmed cell death, is orchestrated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has been implicated in I\/R injury. Here we investigated the mechanisms of cell death pathways in an in vitro model of hepato-steatotic ischaemia. Methods: Free fatty acid (FFA) treated alpha mouse liver 12 (AML-12) cells were incubated in oxygen-glucose-deprivation (OGD) conditions as seen during ischaemia. Results: We found that OGD triggered upregulation of insoluble fraction of RIPK3 and MLKL in FFA + OGD cells compared to FFA control cells. We report that intervention with small interfering (si) MLKL and siRIPK3 significantly attenuated cell death in FFA + OGD cells. Absence of activated CASPASE8 and cleaved-CASPASE3, no change in the expression of CASPASE1 and prostaglandin-endoperoxide synthase 2 (Ptgs2) in FFA + OGD treated cells compared to FFA control cells indicated that apoptosis, pyroptosis and ferroptosis, respectively, are unlikely to be active in this model. Conclusion: Our findings indicate that RIPK3-MLKL dependent necroptosis contributed to cell death in our in vitro model. Both MLKL and RIPK3 are promising therapeutic targets to inhibit necroptosis during ischaemic injury in fatty liver.<\/jats:p>","DOI":"10.3390\/jcm10020212","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T19:55:56Z","timestamp":1610308556000},"page":"212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury"],"prefix":"10.3390","volume":"10","author":[{"given":"Raji","family":"Baidya","sequence":"first","affiliation":[{"name":"Faculty of Medicine, The University of Queensland, Brisbane, Queensland 40006, Australia"},{"name":"Gallipoli Medical Research Institute, Brisbane, Queensland 4120, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7727-9893","authenticated-orcid":false,"given":"J\u00e9r\u00e9mie","family":"Gautheron","sequence":"additional","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA), Inserm, Sorbonne University, 75012 Paris, France"},{"name":"Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell H. G.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Queensland, Brisbane, Queensland 40006, Australia"},{"name":"Gallipoli Medical Research Institute, Brisbane, Queensland 4120, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolu","family":"Wang","sequence":"additional","affiliation":[{"name":"Gallipoli Medical Research Institute, Brisbane, Queensland 4120, Australia"},{"name":"Diamantina Institute, The University of Queensland, Brisbane, Queensland 4102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim R.","family":"Bridle","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Queensland, Brisbane, Queensland 40006, Australia"},{"name":"Gallipoli Medical Research Institute, Brisbane, Queensland 4120, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1007\/s10620-016-4143-0","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations","volume":"61","author":"Sherif","year":"2016","journal-title":"Dig. 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