ArticleHepatology communications2026
Genome-wide CRISPR screen identifies ACSL3 as a regulator of lipotoxicity and progression of MASLD.
Article in Hepatology communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis, are highly prevalent and lack effective pharmacotherapies. Hepatocellular lipotoxicity-driven by the accumulation of saturated fatty acids (eg, palmitate)-promotes disease progression; however, the determinants of hepatocyte susceptibility remain incompletely defined.
methodsWe performed a genome-wide CRISPR-Cas9 loss-of-function screening to identify the regulators of palmitate-induced lipotoxicity. The top candidates were validated using genetic perturbation and pharmacological inhibition. Lipid handling, endoplasmic reticulum/oxidative stress, apoptosis, and lipogenic transcriptional programs were also quantified. Human MASLD liver tissues were analyzed for ACSL3 expression in relation to histology and aminotransferases. Single-cell and spatial transcriptomics were used to localize ACSL3 expression and the associated pathway signatures in metabolic dysfunction-associated steatohepatitis.
resultsThe screen recovered established mediators (CASPASE-8, AGPAT9, RNF213) and identified ACSL3 as a novel determinant of hepatocyte survival under lipotoxic stress. Genetic deletion or pharmacological inhibition of ACSL3 renders hepatocytes resistant to palmitate-induced apoptosis and endoplasmic reticulum stress, accompanied by reduced lipid-droplet accumulation, decreased incorporation of saturated fatty acids into neutral lipids and phospholipids, and blunted induction of lipogenic programs. In human MASLD, hepatic ACSL3 expression positively correlated with histological severity and aminotransferase levels. Single-cell transcriptomics localized ACSL3 predominantly to hepatocytes in advanced metabolic dysfunction-associated steatohepatitis displaying oxidative and endoplasmic reticulum stress signatures, whereas spatial transcriptomics showed ACSL3-high hepatocyte regions enriched for apoptotic and inflammatory pathways and spatially coupled to macrophage-rich and plasma cell-rich niches.
conclusionsACSL3 is a central regulator of lipotoxic hepatocyte injury and MASLD progression, mechanistically linking lipid-droplet biogenesis to apoptosis and inflammatory niche formation. These data suggest that ACSL3 is a promising therapeutic target and support further translational studies to evaluate ACSL3 modulation in steatotic liver disease.
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