NLRP3 inflammasome

Overview

The NLRP3 inflammasome is a multiprotein innate immune signaling complex centered on the NOD-like receptor family pyrin domain containing 3 (NLRP3) sensor protein. It is a key regulator of inflammatory responses because, once activated by diverse cellular stress signals, it promotes assembly of the inflammasome complex, activation of caspase-1, and downstream maturation of pro-inflammatory cytokines such as interleukin-1β, as well as cleavage of Gasdermin D, which contributes to pyroptotic cell death. Because of this central role, NLRP3 inflammasome activation is widely studied in sterile inflammation, metabolic disease, neuroinflammation, fibrosis, and tissue injury.

Biologically, NLRP3 is notable for integrating signals associated with mitochondrial dysfunction, reactive oxygen species, mtDNA release, lysosomal stress, and upstream inflammatory pathways such as NF-κB, TLR2/TLR4, and MyD88-dependent signaling. In recent biomedical research, it has been investigated both as a mechanistic node in disease progression and as a therapeutic target for anti-inflammatory interventions, including small molecules, natural products, exosome-mediated effects, and pathway-directed strategies.

Recent Publications Focus

Below is a summary of the newest research publications targeting NLRP3 inflammasome (sorted by publication date).

Recent studies continue to position NLRP3 inflammasome as a central mediator of inflammatory injury across metabolic, neurologic, renal, and musculoskeletal disease models. In postmenopausal osteoporosis, capsanthin was reported to reduce ovariectomy-induced bone loss in mice, with mechanistic data indicating inhibition of the urotensin II/urotensin II receptor axis, reduced oxidative stress, and suppression of NLRP3 inflammasome activation and pyroptosis, including decreased NLRP3, caspase-1, IL-1β, and Gasdermin D. In diabetic kidney disease models, irbesartan attenuated high-glucose-induced epithelial-mesenchymal transition in HK-2 cells, and this effect was associated with downregulation of NLRP3, caspase-1, and NF-κB p65, with MCC950 producing similar effects. Related metabolic inflammation work also linked high-salt diet to activation of NLRP3 signaling in macrophages, highlighting the inflammasome as a therapeutic node in obesity-associated insulin resistance and chronic inflammation.

Several publications focused on neuroinflammation and cognitive dysfunction. Akkermansia muciniphila improved diabetic cognitive impairment in mice, reduced hippocampal neuroinflammation, and its benefits were lost in NLRP3 knockout animals, supporting a requirement for NLRP3 inflammasome inhibition. Oxytocin alleviated LPS-induced cognitive and synaptic deficits, and MCC950 mimicked its protective effects while nigericin reversed them, implicating suppression of NLRP3-mediated neuroinflammation. quercetin was reported to improve postoperative cognitive dysfunction in aged mice by regulating microglial polarization through ADAR2-mediated editing of miR-379-5p; in this pathway, GSK3β overexpression activated NF-κB/STAT3 signaling and the NLRP3 inflammasome. Additional neuroprotective studies described trans-anethole reducing AlCl3-induced memory impairment by lowering NLRP3, IL-1β, and TNF-α, sulforaphane inhibiting NLRP3 activation through mitophagy and the CBS-H2S axis in Parkinson’s disease models, and glutathione-conjugated gold nanoparticles suppressing the NF-κB/NLRP3 axis in amyloid-beta-induced neuroinflammation and tauopathy in a 3D human neural stem cell model.

Inflammasome modulation was also reported in inflammatory and injury settings outside the nervous system. Ginsenoside Rg3 enhanced cisplatin antitumor activity while mitigating nephrotoxicity in part through SIRT1-dependent suppression of NLRP3 inflammasome activation in HK-2 cells. Bone marrow-derived mesenchymal stem cells reduced radiation pneumonitis by inhibiting NF-κB/NLRP3 signaling and lowering IL-1β, IL-18, and TNF-α. electroacupuncture at ST36 and SP6 alleviated acute gouty arthritis by suppressing NLRP3, caspase-1, and IL-1β and by modulating the circadian-inflammation axis. In hepatic fibrosis, a brominated celastrol derivative blocked stimulus-induced NLRP3 inflammasome activation in hepatic stellate cells and reduced collagen deposition in mice. Other reports linked NLRP3 to vitiligo-associated fibroblast innate immune activation via VDAC1-dependent mitochondrial DNA release and cGAS-STING signaling, and to sepsis-related intestinal barrier dysfunction and pyroptosis through macrophage-derived exosomes.

Recent work also emphasized cell-state and epigenetic regulation of NLRP3-linked inflammation. Aging was shown to reprogram microglia toward an NLRP3+/IL-1β-linked state in traumatic brain injury, with ELF1 identified as a driver of this phenotype and imeglimin improving outcomes in aged mice. In neuropathic pain, neuronal ACVR1-mediated H3K18 lactylation was reported to drive NLRP3-dependent pyroptosis. In a separate pain model, ultrasound-guided human umbilical cord mesenchymal stem cell transplantation reduced NLRP3, ASC, caspase-1, and IL-1β while promoting M2 polarization. Across these studies, NLRP3 inflammasome emerges as a recurring mechanistic hub connecting oxidative stress, mitochondrial dysfunction, macrophage and microglial activation, pyroptosis, and tissue injury, while also serving as a pharmacologically tractable target for natural products, biologics, stem cell-based therapies, and repurposed drugs.

Background PMIDs

[PMID 41570324]
[PMID 41891981]
[PMID 41950807]
[PMID 41973300]
[PMID 42062075]

Method PMIDs

[PMID 41764947]
[PMID 42046270]
[PMID 42294901]

Result PMIDs

[PMID 41638470]
[PMID 41864521]
[PMID 42023556]
[PMID 42043391]
[PMID 42049740]
[PMID 42095873]
[PMID 42126822]
[PMID 42219549]
[PMID 42297939]

Target PMIDs

[PMID 41690453]
[PMID 41722540]
[PMID 41746845]
[PMID 41797134]
[PMID 41825725]
[PMID 41844113]
[PMID 41865457]
[PMID 41875825]
[PMID 41926211]
[PMID 41934900]
[PMID 41967209]
[PMID 41991084]
[PMID 41997056]
[PMID 41997281]
[PMID 42008763]
[PMID 42026634]
[PMID 42049099]
[PMID 42154340]
[PMID 42156155]
[PMID 42169649]
[PMID 42189344]
[PMID 42209865]
[PMID 42224300]
[PMID 42275647]
[PMID 42294901]
[PMID 42300325]
[PMID 42301120]
[PMID 42318962]
[PMID 42410254]