BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death, and its molecular mechanisms have not been fully elucidated. This study aims to elucidate the molecular mechanisms linking pyroptosis and immune microenvironment changes in HCC, with a focus on macrophage polarization and inflammatory responses. METHODS: Selected gene expression profiles from the Gene Expression Omnibus database, established protein-protein interaction (PPI) networks, and performed functional enrichment analysis using databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of relevant hub genes was verified by immunohistochemistry, real-time quantitative PCR, and Western Blot based on clinical tissues. Single-cell identification of HCC cell types and malignant cells, trajectory analysis, and intercellular signal communication further analyzed the molecular mechanisms between immune cells and liver cells. Bioinformatics combined with single-cell analysis to elucidate the immune pyroptosis molecular mechanism that underlay the development of HCC. RESULTS: Molecular biology has identified six pyroptosis hub genes in HCC. The key hub genes of immune pyroptosis were validated through immunohistochemistry and in vitro experiments. Enrichment analysis shows that intersecting genes are enriched in immune responses, chemokine mediated signaling pathways, and inflammatory responses. InferCNV and copyKAT accurately predict that malignant cells distribute in HCC tissues, and their main malignant cells may be hepatocytes, endothelium and epithelial cells. Cell trajectory analysis found that monocyte, macrophage polarization could play a first role in HCC. The cellular clustering of single cells revealed the infiltration of immune cells, especially the polarization of macrophages, which plays an important role. Immunohistochemistry suggests that hub genes such as HMGB1, CYCS, GSDMD, IL-1β, NLRP3, and IL18 are the link between macrophage polarization and pyroptosis during HCC development. CONCLUSIONS: In summary, the main molecular mechanisms underlying the pathogenesis of HCC are related to immune cell infiltration, particularly macrophage infiltration polarization that promotes the secretion of inflammatory factors leading to hepatocyte pyroptosis. These findings provide novel insights into the macrophage-driven pyroptosis pathways in HCC, potentially paving the way for new immunotherapeutic strategies.