ACSS2 induce resistenza al Lenvatinib nel carcinoma epatocellulare attraverso la palmitoilazione.

Lenvatinib, a first-line tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC), faces clinical challenges due to acquired drug resistance. While metabolic reprogramming has been implicated in therapeutic resistance, the precise mechanistic links remain elusive. Here, we identified ACSS2-mediated metabolic-epigenetic crosstalk as a critical driver of Lenvatinib resistance. Transcriptomic and metabolomic profiling identified enhanced pyruvate metabolism in resistant HCC cells, with ACSS2 expression showing the strongest association with Lenvatinib resistance. Genetic manipulation experiments demonstrated that ACSS2 dictates therapeutic sensitivity, with knockdown restoring drug