Decoding pyroptosis at single-cell resolution: heterogeneity, microenvironment remodeling and potential translational insights

Pyroptosis, a pro-inflammatory programmed cell death mediated by inflammatory caspases and Gasdermin (GSDM) family proteins, exerts dual roles in host defense and pathological damage. Traditional bulk RNA sequencing (bulk RNA-seq) is limited in capturing single-cell heterogeneity and dissecting intercellular communication, impeding in-depth mechanistic exploration of pyroptosis. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to address these limitations, enabling high-throughput profiling of single-cell transcriptomes and precise characterization of gene expression heterogeneity, cell subset features, and putative intercellular interaction networks. Here, we comprehensively summarize the cutting-edge applications of scRNA-seq in pyroptosis research from four core aspects: (1) dissecting pyroptosis-related transcriptional heterogeneity with cell subtype and state specificity across diverse cell types and diseases; (2) exploring candidate mechanisms underlying pyroptosis-associated microenvironment remodeling (including immune polarization and stromal reorganization) in pathological progression; (3) harnessing scRNA-seq to construct prognostic pyroptosis-related gene signatures (PRGS) for candidate risk stratification via integration with bulk RNA-seq data; and (4) putative targeted therapeutic strategies (preclinical-stage evidence), including modulation of core pyroptotic nodes, regulation of endogenous modulators, exploitation of exogenous compounds, and indirect interventions through cell function optimization or gut microbiota modulation. Future research should integrate scRNA-seq with multi-omics technologies to construct a multi-dimensional pyroptosis regulatory network, thereby supporting the preclinical development and potential clinical translation of pyroptosis-targeted therapies for inflammation-associated diseases and tumors.