Integrative Multiomics Analysis Reveals a Cancer Stem Cell–Driven Prognostic Signature and Nominates Belinostat for Targeted Therapy in Hepatocellular Carcinoma
TL;DR
This study establishes a novel CSC–associated gene signature for diagnosis and prognosis in HCC and nominates belinostat as a repurposing candidate for targeting stemness‐related pathways, offering a promising strategy for personalized therapy.
Abstract
Background Hepatocellular carcinoma (HCC) suffers from a poor prognosis largely due to its profound molecular heterogeneity and high frequency of relapse, challenges that are closely linked to the biology of cancer stem cells (CSCs) and a lack of effective stemness‐related prognostic biomarkers. Identifying CSC–related prognostic biomarkers and therapeutic targets is critical for improving patient outcomes. Methods We integrated differential expression analysis, weighted gene co‐expression network analysis (WGCNA), and CSC gene databases to identify core prognostic genes driven by stemness mechanisms. A robust prognostic model was developed and validated using multiple machine learning algorithms across TCGA and Gene Expression Omnibus (GEO) cohorts. The clinical relevance of the signature was assessed via receiver operating characteristic curve (ROC) curves, survival analysis, and association with tumor stage. Single‐cell RNA sequencing (scRNA‐seq) and computational drug repositioning coupled with molecular docking were employed to explore mechanistic insights and therapeutic candidates. Results Intersection analysis identified 12 core genes enriched in CSC–associated pathways. The optimal CoxBoost model demonstrated superior predictive performance for overall survival (OS) in internal, external, and meta‐analyses. The signature’s single‐sample GSEA (ssGSEA) score exhibited high diagnostic accuracy, correlated with advanced tumor stage, and enabled effective risk stratification. Single‐cell analysis revealed DARS2 enrichment in M1 macrophages, suggesting a role for CSCs in modulating the tumor immune microenvironment. The histone deacetylase (HDAC) inhibitor belinostat was prioritized via Drug Signature Database (DSigDB) screening and validated by molecular docking as a candidate for targeting the CSC–related signature. Conclusion This study establishes a novel CSC–associated gene signature for diagnosis and prognosis in HCC and nominates belinostat as a repurposing candidate for targeting stemness‐related pathways, offering a promising strategy for personalized therapy.