Targeting pyroptosis: therapeutic potential in the immune-inflammatory imbalance of chronic kidney disease
Abstract
Chronic kidney disease (CKD) is sustained by interacting metabolic, hemodynamic, immune, and fibrotic pathways, yet the contribution of pyroptosis differs substantially across renal compartments and disease contexts. Pyroptosis is a gasdermin-dependent lytic form of regulated cell death that can couple intrinsic renal-cell injury to the release of interleukin-1β, interleukin-18, and damage-associated molecular patterns. This review critically evaluates the evidence linking inflammasome–caspase–gasdermin signaling to diabetic kidney disease, lupus nephritis, IgA nephropathy and membranous nephropathy, crystalline nephropathy, and renal fibrosis. A structured evidence-mapping approach was used to distinguish mechanistic findings from in vitro systems and animal models from observations in human kidney tissue and interventional clinical evidence. Across CKD phenotypes, human studies support pathway activation and cell-type-specific associations, whereas most causal evidence for pyroptosis itself derives from experimental models; this distinction is essential because inflammasome activation or cytokine elevation alone does not establish gasdermin-mediated lytic cell death. Therapeutically, NLRP3, inflammatory caspases, and GSDMD remain attractive targets, but renal translation is still early. Agents such as MCC950, VX-765, disulfiram, and kidney-targeted delivery systems have shown benefit predominantly in preclinical models. The AI-screened GSDMD pore blocker SK56 provides an important proof of concept for effector-stage inhibition, although it has not yet been validated as a CKD therapy. Early clinical development of NLRP3 inhibition in patients with CKD further underscores both the opportunity and the need for rigorous target-engagement, safety, and renal-outcome studies. Future progress will depend on human-anchored biomarkers of gasdermin activation, spatial and single-cell resolution of disease-specific cell states, models that better reproduce multimorbid CKD, and trials that balance anti-inflammatory efficacy against the physiological roles of inflammasome signaling in host defense and tissue repair.
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BibTeX
@article{luo2026targeting,
title = {{Targeting pyroptosis: therapeutic potential in the immune-inflammatory imbalance of chronic kidney disease}},
author = {Yanfang Luo and Xueqin Wu and Wenwei Liu and Muyang Long and Liuting Zeng and Aiming Dai},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1847371},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1847371},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting pyroptosis: therapeutic potential in the immune-inflammatory imbalance of chronic kidney disease
AU - Yanfang Luo
AU - Xueqin Wu
AU - Wenwei Liu
AU - Muyang Long
AU - Liuting Zeng
AU - Aiming Dai
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1847371
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1847371
AB - Chronic kidney disease (CKD) is sustained by interacting metabolic, hemodynamic, immune, and fibrotic pathways, yet the contribution of pyroptosis differs substantially across renal compartments and disease contexts. Pyroptosis is a gasdermin-dependent lytic form of regulated cell death that can couple intrinsic renal-cell injury to the release of interleukin-1β, interleukin-18, and damage-associated molecular patterns. This review critically evaluates the evidence linking inflammasome–caspase–gasdermin signaling to diabetic kidney disease, lupus nephritis, IgA nephropathy and membranous nephropathy, crystalline nephropathy, and renal fibrosis. A structured evidence-mapping approach was used to distinguish mechanistic findings from in vitro systems and animal models from observations in human kidney tissue and interventional clinical evidence. Across CKD phenotypes, human studies support pathway activation and cell-type-specific associations, whereas most causal evidence for pyroptosis itself derives from experimental models; this distinction is essential because inflammasome activation or cytokine elevation alone does not establish gasdermin-mediated lytic cell death. Therapeutically, NLRP3, inflammatory caspases, and GSDMD remain attractive targets, but renal translation is still early. Agents such as MCC950, VX-765, disulfiram, and kidney-targeted delivery systems have shown benefit predominantly in preclinical models. The AI-screened GSDMD pore blocker SK56 provides an important proof of concept for effector-stage inhibition, although it has not yet been validated as a CKD therapy. Early clinical development of NLRP3 inhibition in patients with CKD further underscores both the opportunity and the need for rigorous target-engagement, safety, and renal-outcome studies. Future progress will depend on human-anchored biomarkers of gasdermin activation, spatial and single-cell resolution of disease-specific cell states, models that better reproduce multimorbid CKD, and trials that balance anti-inflammatory efficacy against the physiological roles of inflammasome signaling in host defense and tissue repair.
SN - 1664-3224
ER -