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ASCL2 drives sorafenib resistance through FSAN-mediated MDR1 palmitoylation

GSE326845 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2026/04/17 Platform GPL24676
Summary
Addressing 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.
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Direct links to NCBI, no account and no request form: the whole study as GSE326845_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 6 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1447465 and SRA study SRP688914. Searching any of these in the dataset finder brings you back here.

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