The NLRP3 Inflammasome Across the AKI–AKD–CKD Continuum: Mitochondrial, Epigenetic and Endocrine–Metabolic Regulation
5 affiliations
- 1Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy
- 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- 3Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy
- 4Department of Surgery, Division of Urology, Annunziata Hospital, 87100 Cosenza, Italy
- 5Endocrine and Metabolic diseases Unit, Annunziata Hospital, 87100 Cosenza, Italy
Abstract
The NLRP3 inflammasome has emerged as a potential molecular link between cellular stress, sterile inflammation, and progressive kidney damage. This review critically examines canonical, non-canonical, and mitochondrial mechanisms of NLRP3 regulation across the acute kidney injury (AKI)–acute kidney disease (AKD)–chronic kidney disease (CKD) continuum, integrating their relationships with pyroptosis, maladaptive repair, fibrosis, and epigenetic regulation. Particular attention is given to endocrine–metabolic signals that may shape renal inflammasome activity. Hyperglycemia, advanced glycation end products, mitochondrial reactive oxygen species, TXNIP signaling, lipotoxicity, impaired tubular fatty-acid oxidation, podocyte insulin resistance, obesity-related adipokine imbalance, and aldosterone-mineralocorticoid receptor activation may converge on NLRP3. Conversely, inflammasome-dependent cytokine release and pyroptosis may amplify insulin resistance, metabolic dysfunction, and cardiorenal injury, establishing a bidirectional endocrine-renal inflammatory loop. Importantly, increased NLRP3 mRNA or protein abundance is distinguished from functional inflammasome activation, which is more strongly supported by downstream evidence such as ASC recruitment/oligomerization, caspase-1 activation, mature IL-1β/IL-18 production, GSDMD cleavage, or pyroptotic cell death. A central issue is whether NLRP3 is a causal driver of kidney disease or a marker of ongoing tissue injury. Although genetic and pharmacological studies support a pathogenic role in experimental models, clinical evidence remains largely associative and disease-dependent. NLRP3-related signals should therefore be regarded as candidate, rather than validated, biomarkers. SGLT2 inhibitors, GLP-1 receptor agonists and finerenone may indirectly attenuate NLRP3 signaling, but mechanistic mediation of their clinical benefits remains unproven. Defining cell-specific activation and clinical target engagement will be essential to establish NLRP3 as a biomarker and therapeutic target.
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BibTeX
@article{russa2026nlrp3,
title = {{The NLRP3 Inflammasome Across the AKI–AKD–CKD Continuum: Mitochondrial, Epigenetic and Endocrine–Metabolic Regulation}},
author = {Daniele La Russa and Sabrina Bossio and Antonella La Russa and Michele Di Dio and Daniela Pellegrino and Anna Perri},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209176},
url = {https://www.mdpi.com/1422-0067/27/20/9176},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The NLRP3 Inflammasome Across the AKI–AKD–CKD Continuum: Mitochondrial, Epigenetic and Endocrine–Metabolic Regulation
AU - Daniele La Russa
AU - Sabrina Bossio
AU - Antonella La Russa
AU - Michele Di Dio
AU - Daniela Pellegrino
AU - Anna Perri
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209176
UR - https://www.mdpi.com/1422-0067/27/20/9176
AB - The NLRP3 inflammasome has emerged as a potential molecular link between cellular stress, sterile inflammation, and progressive kidney damage. This review critically examines canonical, non-canonical, and mitochondrial mechanisms of NLRP3 regulation across the acute kidney injury (AKI)–acute kidney disease (AKD)–chronic kidney disease (CKD) continuum, integrating their relationships with pyroptosis, maladaptive repair, fibrosis, and epigenetic regulation. Particular attention is given to endocrine–metabolic signals that may shape renal inflammasome activity. Hyperglycemia, advanced glycation end products, mitochondrial reactive oxygen species, TXNIP signaling, lipotoxicity, impaired tubular fatty-acid oxidation, podocyte insulin resistance, obesity-related adipokine imbalance, and aldosterone-mineralocorticoid receptor activation may converge on NLRP3. Conversely, inflammasome-dependent cytokine release and pyroptosis may amplify insulin resistance, metabolic dysfunction, and cardiorenal injury, establishing a bidirectional endocrine-renal inflammatory loop. Importantly, increased NLRP3 mRNA or protein abundance is distinguished from functional inflammasome activation, which is more strongly supported by downstream evidence such as ASC recruitment/oligomerization, caspase-1 activation, mature IL-1β/IL-18 production, GSDMD cleavage, or pyroptotic cell death. A central issue is whether NLRP3 is a causal driver of kidney disease or a marker of ongoing tissue injury. Although genetic and pharmacological studies support a pathogenic role in experimental models, clinical evidence remains largely associative and disease-dependent. NLRP3-related signals should therefore be regarded as candidate, rather than validated, biomarkers. SGLT2 inhibitors, GLP-1 receptor agonists and finerenone may indirectly attenuate NLRP3 signaling, but mechanistic mediation of their clinical benefits remains unproven. Defining cell-specific activation and clinical target engagement will be essential to establish NLRP3 as a biomarker and therapeutic target.
SN - 1422-0067
ER -