Gasdermin-mediated pyroptosis as a prognostic biomarker and therapeutic target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops within a chronically inflamed and immunologically dysregulated hepatic microenvironment that contributes to therapeutic resistance and disease progression. Gasdermin-mediated pyroptosis has emerged as a context-dependent inflammatory cell-death program capable of reshaping antitumor immunity, stromal remodeling, and immune checkpoint responsiveness. Acute and localized activation of GSDMD or GSDME may enhance immune-cell recruitment and tumor antigen exposure, whereas persistent pyroptotic signaling promotes fibrosis, angiogenesis, and immunosuppressive remodeling. This review examines the molecular circuitry linking pyroptosis with inflammasomes, metabolic stress, mitochondrial dysfunction, hypoxia, and epigenetic regulation in HCC. We further discuss how single-cell and spatial transcriptomic approaches reveal distinct pyroptotic immune niches associated with macrophage polarization, T-cell infiltration, and therapeutic response. Emerging therapeutic strategies including inflammasome modulation, gasdermin-targeted interventions, metabolic sensitization, and combination immunotherapy are also evaluated. Collectively, regulated pyroptosis may represent a promising immunomodulatory framework for improving precision therapy in HCC.