Background <p>Renal fibrosis is key histopathological lesion in chronic kidney disease progression. This study explored pyroptosis-related gene signatures, potential molecular pathways and chemicals, as well as immune infiltration in renal fibrosis.</p> Methods <p>Renal fibrosis datasets and pyroptosis-related genes were obtained and differentially expressed pyroptosis-related genes (DEPGs) were identified. Then functional enrichment analysis was performed and core DEPGs were screened by WGCNA and LASSO regression analysis. Subsequently, miRNA-core DEPG interactions and potential chemicals were established. Finally, immune cell subtype distribution was evaluated and the core DEPGs were externally validated.</p> Results <p>A total of 38 DEPGs were identified which were enriched in inflammatory- and immune-related pathways. Nine core DEPGs were identified and the risk core = (0.1003 × Bak1) + (0.0944 × Zbp1) + (0.0882 × Tlr2) + (0.0585 × Il18) + (0.0497 × Adora2b) + (0.0418 × Stat3) + (0.0325 × Icam1) + (0.0272 × Pycard) + (0.0132 × Epha2). Nine core DEPGs exhibited high sensitivity and specificity for predicting UUO occurrence. A total of 444 miRNA-core DEPG interactions were obtained and miR-124-3p, miR-92a-3p, and miR-6807-5p were identified as core miRNAs. Adenosine served as a potential chemical that directly bound to Adora2b. Immune cells, including naïve B cells, CD4⁺ effector memory T cells, (plasmacytoid) dendritic cells, monocytes, and neutrophils were significantly enriched in fibrotic kidneys. Finally, the differential expression, temporal expression patterns, and clinical correlation with renal function of core DEPGs were externally validated.</p> Conclusions <p>This study sheds light on the novel pyroptosis-related gene signatures in renal fibrosis.</p>