Abstract
Growing evidence has revealed that N6-Methyladenosine (m6A) modification is crucial in cancer development, yet its role in hepatocellular carcinoma (HCC) remains unclear. To address this, we developed a novel m6A regulator-based prognostic signature (m6A-RPS) using comprehensive bioinformatics analysis of TCGA, GEO, and ICGC datasets. Our analysis revealed widespread dysregulation of m6A regulators in HCC tissues. Unsupervised consensus clustering further revealed distinct m6A methylation subtypes with significant survival differences, indicating the potential of m6A modification patterns in prognostic stratification for HCC. Using TCGA-LIHC cohort, LASSO Cox regression selected five key hub regulators (VIRMA, YTHDF1, YTHDF2, YTHDC1, IGF2BP3) to construct the m6A-RPS model. This model proved to be a powerful and independent prognostic indicator (HR = 2.849 (1.819-4.461), P < 0.001), and validated in external cohort (ICGC-LIRI-JP). Patients with high m6A-RPS scores exhibited significantly poorer overall survival and progression-free interval, and the scores were positively correlated with adverse clinical characteristics (e.g., advanced stage, vascular invasion). To facilitate clinical translation, we developed a nomogram that integrated the m6A-RPS with key clinical variables for individualized survival prediction. Genomically, the high-risk group exhibited higher tumor mutation burden and mutation rates in hub regulators. Functional enrichment analyses implicated dysregulation in critical pathways like Wnt signaling, DNA replication, and cell cycle. Crucially, m6A-RPS stratified the tumor immune microenvironment: high-risk patients displayed an immunosuppressive phenotype characterized by enriched Th2 cells and higher potential for immune escape, whereas low-risk patients showed enhanced cytotoxic immune infiltration and elevated immunophenoscores, suggesting greater potential responsiveness to immune checkpoint inhibitors. Differential sensitivity to chemotherapy agents was also predicted. Finally, we constructed a regulatory network linking miRNAs, hub regulators, and 2 downstream target genes. Our study establishes m6A-RPS as a robust tool for prognosis prediction and immune landscape assessment in HCC, offering significant potential to guide personalized therapeutic strategies, particularly immunotherapy selection.