Multi-omics Analysis Revealed the Diagnostic and Therapeutic Value of Immunogenic Cell Death-derived SCN5A in Hepatocellular Carcinoma

This study explores the diagnostic and therapeutic potential of SCN5A, an immunogenic cell death (ICD)-related gene, in hepatocellular carcinoma (HCC). Integrated analysis of four databases identified 62 ICD-associated genes (ICDGs), with SCN5A emerging as a key player linked to HCC prognosis and immune microenvironment modulation. Single-cell RNA sequencing revealed correlations between ICD activity and tumor immune dynamics. Bulk RNA sequencing categorized HCC into distinct molecular subtypes with varied immunological features. Machine learning-based prognostic models highlighted SCN5A's clinical relevance, supported by phenome-wide association studies connecting SCN5A to liver malignancies. Experimental validation showed elevated SCN5A expression in HepG2 cells, where siRNA-mediated knockdown significantly impaired proliferation (CCK8 and colony formation assays), invasion (Transwell), migration (wound healing), and apoptotic index (TUNEL assays and Bax, Bcl-2 expression). Molecular docking identified propafenone as a high-affinity SCN5A binder, which suppressed SCN5A expression and mirrored knockdown effects by inhibiting HCC cell growth and metastasis while promoting apoptosis. These findings position SCN5A as a novel ICD-linked biomarker and therapeutic target in HCC, with propafenone repurposing showing promising anti-tumor efficacy through SCN5A modulation. This work bridges computational biology with experimental oncology to advance ICD-targeted HCC treatment strategies.