Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer worldwide, with high incidence and mortality. Pyroptosis, a form of inflammatory-regulated cell death, is closely associated with oncogenesis.

Methods: Expression profiles of HCC were downloaded from the TCGA database and validated using the ICGC and GEO databases. Consensus clustering analysis was used to determine distinct clusters. The pyroptosis-related genes (PRGs) included in the pyroptosis-related signature were selected by univariate Cox regression and LASSO regression analysis. Kaplan-Meier and receiver operating characteristic (ROC) analyses were performed to estimate the prognostic potential of the model. The characteristics of infiltration of immune cells between different groups of HCC were explored.

Results: Two independent clusters were identified according to PRG expression. Cluster 2 showed upregulated expression, poor prognosis, increased immune cell infiltration and worse immunotherapy response than cluster 1. A prognostic risk signature consisting of five genes (GSDME, NOD1, PLCG1, NLRP6 and NLRC4) was identified. In the high-risk score group, HCC patients showed decreased survival rates. In particular, multiple clinicopathological characteristics and immune cell infiltration were significantly associated with the risk score. Notably, the 5 PRGs in the risk score have been implicated in carcinogenesis, immunological pathways and drug sensitivity.

Conclusions: A prognostic signature comprising five PRGs can be used as a potential prognostic factor for HCC. The PRG-related signature provides an in-depth understanding of the association between pyroptosis and chemotherapy or immunotherapy for HCC patients.