Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, with survival rates still falling short of expectations. Emerging evidence highlights the pivotal roles of both m6A methylation and ferroptosis-related genes (FRGs) in HCC progression. However, the prognostic significance of m6A-modulated FRGs remains largely unexplored. In this study, we developed a novel prognostic signature based on m6A-regulated FRGs, identifying six key genes (VEGFA, FANCD2, ZFP69B, EIF2S1, SLC7A11, and SRXN1) through multivariate and LASSO Cox regression analyses. A high m6A-FRGs score was strongly associated with poor prognosis, and multivariate analysis confirmed it as an independent prognostic factor. Notably, the high-risk group exhibited increased expression of immune checkpoint genes and a higher frequency of gene mutations. Functional assays further demonstrated that silencing ZFP69B significantly suppressed liver cancer cell proliferation, migration, and invasion. Clinical validation in 144 HCC samples revealed that elevated ZFP69B expression correlated with worse patient outcomes. Moreover, qPCR analysis confirmed CLSPN and HNRNPR as downstream targets of ZFP69B. Collectively, our findings establish the m6A-FRGs signature as a powerful prognostic tool for HCC and identify ZFP69B as a promising therapeutic target, warranting further investigation.