Recent advances in PANoptosis research in kidney disease: mechanistic networks, pathological roles, and potential intervention strategies

Abstract

PANoptosis is an integrated inflammatory form of programmed cell death mediated by the PANoptosome, which coordinates the core molecular networks of pyroptosis, apoptosis, and necroptosis. In recent years, PANoptosis-related signaling has been implicated in a wide range of renal pathological processes, including sepsis-associated acute kidney injury, ischemia–reperfusion injury, drug- or toxin-induced nephropathy, diabetic nephropathy, chronic kidney disease, renal fibrosis, and clear cell renal cell carcinoma. Mechanistically, these processes may involve the coordinated activation of key molecules, including ZBP1, AIM2, RIG-I, RIPK1, CASP8, NLRP3, GSDMD/GSDME, and RIPK3/MLKL. However, most existing studies remain largely confined to marker co-expression, animal models, or bioinformatics-based analyses, while direct evidence of PANoptosome assembly and functional dependence remains limited. Notably, the predominant cell types, upstream stimuli, and biological consequences of PANoptosis vary substantially across disease contexts. In non-neoplastic kidney diseases, PANoptosis is commonly associated with inflammatory injury and fibrotic progression; in contrast, in clear cell renal cell carcinoma, PANoptosis-related molecular signatures are more frequently linked to prognostic stratification and prediction of immunotherapy response. Future studies should place greater emphasis on validating PANoptosome assembly, defining cell lineage-specific localization, establishing temporal causality, and confirming findings in clinical samples. Integrating single-cell multi-omics, spatial transcriptomics, and functional intervention models will help advance PANoptosis from a mechanistic concept toward precise kidney disease subtyping and network-based targeted therapeutic strategies.