DOI: 10.1097/hep.0000000000001830 ISSN: 0270-9139

Hepatocyte MLKL drives obesity-driven hepatocellular carcinoma progression via mitochondrial dysfunction independent of necroptosis in MASLD

Phoebe Ohene-Marfo, Sabira Mohammed, Chao Jiang, Shylesh Bhaskaran, Kara Kneuper, Satoshi Matsuzaki, Bo Hagy, Randal J. May, Constantin Georgescu, Megan John, Julianne N. Hoang, Kevin Pham, Albert Tran, Chinthalapally V. Rao, Tae Gyu Oh, Michael Kinter, Willard M Freeman, Courtney Houchen, Surendra Shukla, Kenneth Humphries, Jonathan D Wren, Sathyaseelan S. Deepa
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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, yet mechanisms linking hepatocyte dysfunction to tumorigenesis remain unclear. 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.

Approach and Results:

Using a long-term Western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout ( Mlkl HepKO ) mice, we defined MLKL’s 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 Mlkl HepKO mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness. Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in Mlkl HepKO 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.

Conclusions:

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.

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