BACKGROUND: This study sought to establish a risk score signature based on disulfidptosis-related genes (DRGs) to predict the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: The expression data of DRGs from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) was analyzed to develop and validate a DRG prognostic signature (DRGPS). In vitro, experiments were conducted to explore DRG expressions and roles in HCC tissues and cell lines. HCC tissue microarrays were employed to analyze SLC7A11 expression and its association with clinicopathological characteristics. RESULTS: The DRGPS consisted of 5 DRGs (SLC7A11, MATN3, CLEC3B, CCNJL, and PON1). The survival rate of HCC patients in high-risk group was significantly lower than that in low-risk group. The DRGPS was also associated with the modulation of tumor microenvironment (TME), tumor mutation burden (TMB), stemness and chemosensitivity. Furthermore, pan-cancer analysis suggested that the DRGPS risk score was associated with immune infiltration and stemness in multiple cancers. Moreover, our DRGPS had potential for predicting treatment efficacy in HCC patients. Finally, we confirmed that downregulation of SLC7A11, a DRG, inhibited the proliferation and migration of HCC cells, while its high expression correlated with advanced TNM clinical stage and larger tumor size. CONCLUSIONS: This study systematically describes a novel DRGPS constructed for predicting HCC prognosis, providing a new approach to risk stratification and treatment options. It also investigates the expression and function of SLC7A11, contributing to further exploration of the molecular mechanism underlying disulfidptosis in HCC, as well as its prognostic and therapeutic implications.