GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326845/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326845GEOGSEfalseASCL2 drives sorafenib resistance through FSAN-mediated MDR1 palmitoylationAddressing sorafenib resistance—a major barrier to effective treatment of hepatocellular carcinoma (HCC)—this study utilized patient-derived liver cancer stem cell (LCSC) models to elucidate the pivotal role of the transcription factor ASCL2 in maintaining stemness and driving drug resistance. 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.2026/04/17GSE326845GSM9641250GSM9641249GSM9641246GSM9641245GSM9641248GSM964124724676326845Homo sapiens