ASCL2 drives sorafenib resistance through FSAN-mediated MDR1 palmitoylation

Through integrated transcriptomic and epigenomic analyses, we discovered that ASCL2 orchestrates a resistance program by directly activating the transcription of fatty acid synthase (FASN) alongside palmitoyltransferases (ZDHHC5/9) and the multidrug resistance protein (MDR1), thereby transcriptionally "coupling" lipogenesis to protein modification.

Mechanistically, ASCL2 promotes MDR1 palmitoylation and its subsequent membrane localization via FASN-driven palmitate production, ultimately leading to sorafenib resistance; conversely, pharmacological inhibition of palmitoylation disrupted MDR1 membrane localization and restored drug sensitivity in patient-derived LCSCs. These findings delineate a novel mechanism by which ASCL2 coordinates lipid metabolic reprogramming with post-translational modifications to drive therapeutic resistance, providing a potential interventional strategy to overcome sorafenib resistance by targeting LCSCs in HCC.