Hepatocellular carcinoma (HCC) is a type of liver cancer that originates from liver cells. It is one of the most common types of liver cancer and a leading cause of cancer-related death worldwide. Early detection and treatment can improve the HCC prognosis. Therefore, it is necessary to further improve HCC markers and risk stratification. PANoptosome is a cytoplasmic polymer protein complex that regulates a proinflammatory programmed cell death pathway called “PANoptosis”. The role of PANoptosis in HCC remains unclear. In this study, the molecular changes of PANoptosis related genes (PAN-RGs) in HCC were systematically evaluated. We characterized the heterogeneity of HCC by using consensus clustering to identify two distinct subtypes. The two subtypes showed different survival rate, biological function, chemotherapy drug sensitivity and immune microenvironment. After identification of PAN-RG differential expression genes (DEGs), a prognostic model was established by Cox regression analysis using minimum absolute contraction and selection operator (LASSO), and its prognostic value was verified by Cox regression analysis, Kaplan-Meier curve and receiver operating characteristic (ROC) curve. Our own specimens were also used to further validate the prognostic significance and possible clinical value of the selected targets. Subsequently, we conducted a preliminary discussion on the reasons for the influence of the model on the prognosis through TME analysis, drug resistance analysis, TMB analysis and other studies. This study provides a new idea for individualized and precise treatment of HCC.