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Mixed lineage kinase domain-like protein (MLKL), the effector of necroptosis, is elevated in MASLD, but its hepatocyte-intrinsic role in obesity-driven MASLD-HCC is unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Approach and Results<\/jats:title>\n                  <jats:p>\n                    Using a long-term Western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout (\n                    <jats:italic>\n                      Mlkl\n                      <jats:sup>HepKO<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice, we defined MLKL\u2019s hepatocyte-intrinsic function. WD increased hepatocyte MLKL protein expression without detectable necroptosis activation, indicating a necroptosis-independent role. MLKL deficiency did not alter WD-induced inflammation, fibrosis, or liver injury but increased hepatic lipid accumulation while reducing lipotoxic lipid species and preserving mitochondrial function. WD-fed\n                    <jats:italic>\n                      Mlkl\n                      <jats:sup>HepKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness. Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in\n                    <jats:italic>\n                      Mlkl\n                      <jats:sup>HepKO<\/jats:sup>\n                    <\/jats:italic>\n                    livers. WD suppressed the mitochondrial fusion protein and tumor suppressor MFN2, whereas MLKL deficiency restored MFN2 expression post-translationally. In HCC cells, MLKL deletion reduced proliferation, improved mitochondrial respiration, and decreased glycolysis; these effects were reversed by MFN2 deletion. MLKL localized to nuclear and mitochondrial compartments, consistent with organelle-intrinsic functions. The human MLKL inhibitor necrosulfonamide (NSA) suppressed HepG2 xenograft growth, and elevated MLKL expression in human HCC correlated with poorer overall survival.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Hepatocyte MLKL promotes MASLD-associated HCC through a non-necroptotic mechanism involving MFN2 suppression, impaired mitochondrial function, and increased tumor proliferation and stemness. These findings identify MLKL as a potential therapeutic target in MASLD-associated HCC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.26.690789","type":"posted-content","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T04:05:10Z","timestamp":1764561910000},"source":"Crossref","is-referenced-by-count":2,"title":["Hepatocyte MLKL Drives Obesity-Driven Hepatocellular Carcinoma Progression via Mitochondrial Dysfunction Independent of Necroptosis in MASLD"],"prefix":"10.64898","author":[{"given":"Phoebe","family":"Ohene-Marfo","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Physiology, The University of Oklahoma Health Campus"},{"name":"Stephenson Cancer Center, The University of Oklahoma Health Campus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabira","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, The University of Oklahoma Health 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