Hepatocyte MLKL Drives Obesity-Driven Hepatocellular Carcinoma Progression via Mitochondrial Dysfunction Independent of Necroptosis in MASLD
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Background and Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), particularly in obesity. Mixed Lineage Kinase Domain Like (MLKL), the effector of proinflammatory cell death pathway necroptosis, is consistently elevated in human and experimental MASLD, yet the hepatocyte-specific role of MLKL in the neoplastic progression of MASLD to HCC in obesity is unknown.
Approach and Results
We used a long-term WD-induced, MASLD-driven HCC model in which mice develop liver cancer at ages comparable to human HCC onset. Hepatocyte-specific MLKL knockout ( Mlkl HepKO ) mice were generated to define MLKL’s liver-intrinsic function. WD robustly induced hepatic MLKL, whereas necroptosis markers were undetectable. MLKL loss did not alter WD-induced inflammation, fibrosis, or liver injury but markedly increased lipid droplet accumulation. Strikingly, Mlkl HepKO mice developed significantly fewer and smaller tumors with reduced stemness markers (DCLK1, OCT4). Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in WD-fed Mlkl HepKO livers. WD suppressed the mitochondrial fusion protein and tumor suppressor Mfn2, while MLKL deficiency restored its expression. In HepG2 cells, MLKL knockdown or inhibition reduced proliferation and clonogenicity and enhanced oxidative metabolism. Human HCC datasets and tissue microarrays showed elevated MLKL in tumors and its association with poor survival.
Conclusions
Hepatocyte MLKL drives MASLD-driven HCC progression by an intrinsic, non-necroptotic mechanism. The mechanism involves MLKL-mediated suppression of the Mfn2 tumor suppressor protein, impaired mitochondrial respiration, and increase in both tumor cell proliferation and tumor stemness. All together these data position MLKL as a novel, druggable target in MASLD-associated HCC.
Abstract Figure
GRAPHICAL ABSTRACT:Graphical illustration of the proposed mechanism of the role of MLKL in WD-induced MASLD driven HCC.
