NOD-like receptor pyrin domain-containing 3

Overview

NOD-like receptor pyrin domain-containing 3 (NLRP3) is a cytosolic pattern-recognition receptor and a central component of the NLRP3 inflammasome. In innate immune signaling, NLRP3 helps sense diverse cellular stressors and danger-associated signals, leading to inflammasome assembly and downstream activation of caspase-1, with subsequent maturation of pro-inflammatory cytokines such as interleukin-1β. Because of this role, NLRP3 is widely studied as a mediator of sterile inflammation, metabolic inflammation, neuroinflammation, and tissue injury.

In biomedical research, NLRP3 is frequently investigated as a therapeutic target rather than as a standalone biomarker. Recent studies in the provided corpus place NLRP3 within pathways such as TLR4/NF-κB/NLRP3, TLR4-dependent inflammasome signaling, AMPK-mTOR, and HSP90-mediated protein stability. These studies collectively support the view that NLRP3 integrates upstream inflammatory cues and contributes to disease progression in interstitial cystitis/bladder pain syndrome, epilepsy-associated neuroinflammation, steatohepatitis, osteoporosis, ischemia/reperfusion injury, hyperuricemic nephropathy, and other inflammatory conditions.

Focus of Latest Publications

Recent publications continue to position NOD-like receptor pyrin domain-containing 3 (NLRP3) as a central inflammatory target across diverse disease models. Several studies evaluated strategies that suppress NLRP3 inflammasome activation to reduce tissue injury and inflammatory signaling. In dextran sulfate sodium-induced colitis, donkey milk exosomes were reported to deliver eca-miR-148a, which directly targeted the NLRP3 3'UTR and suppressed the NLRP3-Caspase-1-IL-18 axis, alongside improvements in intestinal barrier integrity, cytokine profiles, oxidative stress, and gut microbiota composition. In hyperuricemic nephropathy, p-coumaric acid was investigated as a means to target Cathepsin B and rescue WWP1-dependent proteasomal degradation of NLRP3, although the abstract provided does not include the full experimental outcomes. In osteoporosis-related osteoblast injury, betulinic acid reduced NLRP3, ASC, and caspase-1 expression, lowered inflammatory mediators, and improved osteogenic differentiation, with the effect linked to autophagy activation through the AMPK/mTOR pathway.

Other studies examined NLRP3 in neurological and age-related inflammatory disorders. In aged mice, liraglutide alleviated postoperative cognitive impairment by activating the GLP-1R/NRF2 pathway, reducing reactive oxygen species, and suppressing NLRP3 inflammasome components; these effects were reversed by the NRF2 inhibitor ML385 and were dependent on microglia. Thymol nanoparticles also improved oxaliplatin-induced cognitive impairment in rats, with reported modulation of oxidative stress, endoplasmic reticulum stress, and NLRP3 inflammasome signaling. In vascular dementia models, the traditional formula Naokang II decoction was analyzed by network pharmacology and in vitro validation, identifying NLRP3 as a core target in microglia; the coumarin Herniarin showed the strongest docking affinity to NLRP3 and downregulated TLR2, NLRP3, ASC, and CASP1 in microglial cells.

NLRP3 was also implicated in aging and senescence-associated inflammation. A study of Nlrp3 haploinsufficiency in mice found that partial reduction of NLRP3, rather than being uniformly protective, could unmask compensatory NLRP1 overexpression and a hybrid NLRP1-NLRP3 inflammasome interaction that drove accelerated inflammatory aging by 16 months of age. This work suggested that partial NLRP3 inhibition may have unintended consequences and that broader inflammasome targeting could be more effective for age-related disease. In ovarian granulosa cells from aged patients, NPY1R overexpression activated CREB signaling and increased IL-6 and NLRP3 expression, contributing to ferroptosis, mitochondrial dysfunction, and ovarian aging. In a separate biomaterials study, MCC950, a selective NLRP3 inhibitor, was incorporated into silk microgel-hydrogel scaffolds; the construct retained bioactivity, reduced NLRP3 expression around implants, decreased fibrous capsule formation, and increased cellular infiltration in vivo, supporting a pro-regenerative immune microenvironment.

Across these publications, NLRP3 emerges as a convergent node linking oxidative stress, cytokine production, pyroptosis, fibrosis, and tissue remodeling. The studies collectively highlight multiple intervention modes, including miRNA delivery, natural products, small-molecule inhibitors, hormone-like agonists, and biomaterial-based local drug delivery. While most reports describe suppression of NLRP3 as beneficial, the aging study underscores that the biological consequences of partial NLRP3 inhibition may be context dependent, especially when compensatory inflammasome pathways are engaged.

Key Publications

• NEWJul Donkey Milk Exosomes Protect Against Dextran Sulfate Sodium-Induced Colitis by Delivering Anti-Inflammatory miRNAs and Reshaping Gut Microbiota. (Journal of food science, 2026, PMID 42378030): "Mechanistically, eca‐let‐7g directly targeted TLR4 3'UTR to inhibit NF‐κB, while eca‐miR‐148a targeted NLRP3 3'UTR to suppress the NLRP3‐Caspase‐1‐IL‐18 axis."
• NEWJun NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice. (Science advances, 2026, PMID 42361162): "although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized."
• NEWJun Targeting Cathepsin B with p-coumaric acid rescues WWP1-dependent proteasomal degradation of NLRP3 in hyperuricemic nephropathy. (Molecular medicine (Cambridge, Mass.), 2026, PMID 42363040): "...driven primarily by aberrant NLR family pyrin domain containing 3 (NLRP3) inflammasome activation."
• NEWJun Mechanism and Intervention of the NPY1R/CREB Signaling Axis in Regulating Inflammatory Response in Aged Ovarian Granulosa Cells and Ovarian Senescence. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42262763): "promotes the expression of pro-inflammatory factor IL-6 and inflammasome NLRP3, aggravates ferroptosis, mitochondrial dysfunction, and type I/III collagen imbalance, and ultimately accelerates ovarian aging."
• Jun MCC950-loaded silk microgel-hydrogel composite scaffolds effectively modulate inflammation for improving tissue interaction and remodeling. (Acta biomaterialia, 2026, PMID 42242405): "...attributed to the decrease in NLRP3 expression around the scaffold."
• May Thymol nanoparticles ameliorate oxaliplatin-induced cognitive impairment via modulation of Nrf2/HO-1, endoplasmic reticulum stress, and NLRP3 inflammasome signaling in rats. (Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2026, PMID 42202464): "The substantial impact of THY on modulating neuroinflammation cues was also evident by its effect on the NLR family pyrin domain-containing 3 (NLRP3) inflammasome pathway."
• May Disruption of upstream ox-LDL signaling and HSP90-mediated NLRP3 stability protects against experimental steatohepatitis. (Naunyn-Schmiedeberg's archives of pharmacology, 2026, PMID 42183856): "Mechanistically, the combination targets two distinct but converging levels of inflammasome regulation: FLU reduces ox-LDL, a key upstream activator of NLRP3, whereas ALV destabilizes the client protein NLRP3 by inhibiting its molecular chaperone HSP90."
• May Betulinic acid alleviates the inflammatory injury of osteoblasts in osteoporosis by augmenting autophagy via the AMPK-mTOR signaling pathway. (International journal of molecular medicine, 2026, PMID 42138188): "BA was revealed to alleviate bone loss in OVX rats and inhibit the expression of NOD-like receptor pyrin domain-containing 3 (NLRP3), Asc and caspase-1 in the femur of OVX rats, as well as suppress the release of inflammatory factors such as interleukin-1 β, interleukin-6, and tumor necrosis factor-α in the serum of rats."
• May An Integrated Approach Combining Chemical Profiling, Network Pharmacology, and In Vitro Validation to Uncover the Multitarget Mechanisms of Naokang II Decoction against Vascular Dementia. (Journal of natural products, 2026, PMID 42099108): "Molecular docking revealed that the coumarin Herniarin, a component newly identified in NKII, exhibited the strongest binding affinity to NLRP3."
• May Liraglutide alleviates postoperative cognitive impairment via NRF2/NLRP3 signal pathway in aged mice. (Neuroscience letters, 2026, PMID 42102962): "Molecular analysis showed that LIR activated the GLP-1R/NRF2 pathway, reduced reactive oxygen species (ROS) accumulation, and suppressed the expression of NLRP3 inflammasome components."