Lattilazione converte ABHD6 in un regolatore mitocondriale che promuove la resistenza al lenvatinib nel carcinoma epatocellulare.

UNLABELLED: Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a first-line tyrosine kinase inhibitor. Resistance arises from heterogeneous mechanisms involving metabolic reprogramming and mitochondrial adaptation, implicating regulators of these processes as potential therapeutic targets. In this study, we identified α/β hydrolase domain containing 6 (ABHD6) as a critical driver of lenvatinib resistance by perturbing mitochondrial dynamics. Ligand binding at the S148 catalytic site allosterically controlled a molecular switch between canonical enzymatic and noncanonical scaffolding functions of ABHD6, and the proresistance function was independent of catalysis but