Transcriptomic Profiling Identifies CSNK1E as a Key Mediator of Sorafenib Resistance in Hepatocellular Carcinoma

Background Sorafenib is the standard first-line therapy for advanced hepatocellular carcinoma (HCC), yet its clinical efficacy is often limited by primary or acquired resistance. The molecular mechanisms underlying this resistance remain poorly understood. Casein kinase 1 epsilon (CSNK1E), a known regulator of WNT/β-catenin signaling, may play a role in drug resistance, but its function in sorafenib response in HCC is unclear. Methods We analyzed transcriptomic data from 67 HCC patients treated with sorafenib, including 21 responders and 46 non-responders. Differential expression and LASSO regression analyses, integrated with TCGA data and protein-protein interaction networks, were used to identify resistance-related genes. Functional validation of CSNK1E was conducted using in vitro assays and xenograft models. Results A panel of eight genes ALDOA, BRD9, CSNK1E, DRAP1, FLNC, RPL27, THBS3, and ZRANB2 was identified to be significantly upregulated in non-responders and associated with poor clinical outcomes. Among these, CSNK1E exhibited the highest prognostic relevance. Elevated CSNK1E expression was associated with unfavorable survival, increased TP53 mutation frequency, and copy number instability. Functional assays demonstrated that CSNK1E promoted HCC cell proliferation, migration, and resistance to sorafenib. Gene set enrichment analysis indicated that high CSNK1E expression was linked to activation of oncogenic pathways including WNT signaling and cell cycle progression. Conclusion CSNK1E is a key mediator of sorafenib resistance in HCC. Our eight-gene signature may serve as a predictive biomarker panel for sorafenib efficacy, offering a basis for personalized treatment strategies in HCC.