• • LY96 overexpression in HCC tissues correlates with reduced overall survival (OS) in TCGA cohorts, establishing it as a prognostic biomarker with direct clinical utility for risk stratification.
• • Mechanistic validation via GSEA and experimental assays confirms LY96-driven activation of TGF-β1/Smad2/3 signaling, a pathway amenable to pharmacological interruption with L6H21.
• • Lipid-polymer hybrid nanoparticles achieve systemic delivery of L6H21, demonstrating significant suppression of HCC progression in both in vitro and in vivo models, with potential to overcome bioavailability barriers of small-molecule inhibitors.
• • The integration of cancer-immunity cycle scoring with WGCNA provides a systems-level framework for target discovery, yielding LY96 as a node linking immunogenic cell death to oncogenic signaling.