Identification of prognostic signatures of ferroptosis and autophagy-dependent lipid metabolism-related genes in hepatocellular carcinoma

The regulatory role of ferroptosis and autophagy in lipid metabolism during hepatocellular carcinoma (HCC) progression remains largely unexplored. Through integrated analysis of TCGA, MsigDB, FerrDb, and HADb datasets, we identified 33 ferroptosis and autophagy-dependent lipid metabolism-related genes (Fer-Aut-LMRGs) with prognostic significance. A novel two-gene (TXNRD1 and ALAS1) prognostic model was developed using Cox and LASSO regression analyses and validated in the ICGC cohort. The risk score emerged as an independent prognostic factor, effectively stratifying patients and correlating with immune microenvironment features, immunotherapy response, and drug sensitivity. High-risk patients exhibited enhanced immune escape potential and reduced response to immune checkpoint inhibition. Single-cell analysis revealed dynamic evolution of tumor and immune cell populations during HCC progression. Experimental validation confirmed the expression patterns of model genes and demonstrated ALAS1's functional role in regulating HCC cell invasion and migration. These findings establish a crucial link between ferroptosis, autophagy, and lipid metabolism in HCC, providing a robust prognostic tool and potential therapeutic targets for personalized HCC management. The study highlights the clinical relevance of integrating multi-omics approaches with functional validation in cancer research.