The NLRP3 inflammasome in chronic kidney disease progression: systematic review of preclinical models reveals a critical gap in pyroptosis research and therapeutic translation.

Authors

Sagar A More, Arti Patil, Manish Joshi, Prajwal Dhokne, Vijaykumar D Nimbarte, Shrikant R Mulay

Published in

Molecular biology reports. Volume 53. Issue 1. Aug 04, 2026. Epub Aug 04, 2026.

Abstract

Chronic kidney disease (CKD) affects ~ 850 million people globally. The NOD-like receptor protein 3 (NLRP3) inflammasome has emerged as a central regulator of inflammatory, fibrotic, and mitochondrial injury during CKD pathogenesis. Nevertheless, its consistency across disease models and translational status has not been systematically evaluated to date. We conducted a PubMed and Scopus search for research articles examining NLRP3 inflammasome activation across various CKD models, following PRISMA guidelines, and selected 17 animal studies for further analysis. We found that across all model types, NLRP3 activation was consistently associated with upregulated caspase-1, elevated IL-1β and IL-18, and a decline in renal function, tubular injury, interstitial fibrosis, and mitochondrial dysfunction. Inflammation was reported in renal tubular epithelial cells, infiltrating macrophages, and glomerular cells. Furthermore, both genetic and pharmacological inhibition of NLRP3 reproducibly attenuated CKD, establishing a causal role rather than association of NLRP3 inflammasome in CKD progression. Surprisingly, although pyroptosis is the canonical effector arm of NLRP3 signalling, no included CKD study directly assessed pyroptosis or gasdermin D-mediated cell death, highlighting a fundamental mechanistic gap. Furthermore, despite multiple preclinical studies, only AZD4144, an AstraZeneca NLRP3 inhibitor, is currently in clinical trials for CKD. Overall, NLRP3 is a validated driver of CKD progression across diverse models. The lack of evaluation of NLRP3-mediated pyroptosis in CKD, along with limited clinical trials evaluating NLRP3 inflammasome inhibitors, highlights key research and translational gaps in CKD treatment.

PMID:
42550320
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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