A Reliable Prognostic Model for Hepatocellular Carcinoma Using Neutrophil extracellular traps and immune Related Genes

Background Neutrophil extracellular traps (NETs) and immunity play critical roles in liver hepatocellular carcinoma (LIHC) progression, but their mechanisms remain unclear. This study explored the potential of NETs-related genes (NETs-RGs) and immune-related genes (IRGs) as prognostic markers for LIHC. Methods LIHC transcriptome data and IRGs were obtained from public databases, and NETs-RGs were derived from prior research. Differentially expressed genes (DEGs) intersecting with key module genes were identified, followed by Cox regression analysis and machine learning to determine prognostic genes. A risk prediction model and nomogram were constructed and validated. Enrichment analysis, immune infiltration, and drug sensitivity studies were conducted to explore underlying mechanisms. Reverse transcription quantitative PCR (RT-qPCR) was used to validate findings. Results Five prognostic genes— HMOX1 , MMP9 , TNFRSF4 , MMP12 , and FLT3 —were identified. A risk model and nomogram demonstrated strong predictive ability. Gene set enrichment analysis revealed pathways related to retinol metabolism and cytochrome P450 drug metabolism in different risk groups. Immune infiltration analysis showed regulatory T cells positively correlated with MDSCs, which were directly associated with the five genes. Drug sensitivity analysis identified 74 drugs with differential sensitivity between risk groups; axitinib showed lower sensitivity in high-risk patients, while ABT-888 showed higher sensitivity. RT-qPCR confirmed reduced HMOX1 and FLT3 expression in LIHC tissues, while MMP9 and TNFRSF4 were upregulated. Conclusion This study developed a robust predictive model for LIHC prognosis, offering valuable insights for clinical management and personalized treatment strategies.