ACSS2 drives Lenvatinib resistance in hepatocellular carcinoma through palmitoylation.

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 response and overexpression conferring resistance. Mechanistically, ACSS2-driven palmitate biosynthesis facilitates EGFR palmitoylation, which shields the receptor from ubiquitin-dependent degradation. This stabilization sustains oncogenic EGFR signaling, ultimately mediating therapeutic escape. Crucially, pharmacological inhibition of ACSS2 synergized with Lenvatinib to overcome resistance in both subcutaneous and hydrodynamic transfection HCC models. Our findings not only delineate the ACSS2/EGFR axis as a metabolic vulnerability in resistant HCC but also propose ACSS2-targeted therapy as a promising strategy to reverse Lenvatinib resistance, providing a novel therapeutic approach for advanced HCC management.