Targeting the NLRP3 inflammasome in kidney disease: molecular mechanisms, pathogenic roles, and emerging small-molecule therapeutics

The glomerular capillary wall is composed of endothelial cells, the basement membrane, and visceral epithelial cells (podocytes), surrounded by mesangial cells and matrix. Li Fang et al. detected the expression of caspase-1, IL-1β, and IL-18 in DN renal tubules, which positively correlated with the severity of proteinuria. In the same specimens, the expression of inflammatory factors was higher in renal tubules than in glomeruli (120). Hong Feng et al. were the first to demonstrate that high glucose induces the expression and activation of NLRP3 and pro-caspase-1 in mesangial cells, leading to the release of IL-18, increased glomerular and mesangial area, and enhanced collagen accumulation in the kidney (121). Chenlin Gao et al. found that receptor-interacting protein kinase 2 (RIPK2)-mediated podocyte autophagy negatively regulates ROS-NLRP3 inflammasome signaling under high-glucose conditions. High glucose activates autophagy in the short term but suppresses it over prolonged periods. Activation of NLRP3 inhibits podocyte autophagy, weakening the protective effects mediated by autophagy and exacerbating podocyte damage (122). Chun Zhang et al. observed foot process effacement, loss of slit diaphragm molecules, and glomerulosclerosis in mice following homocysteine-induced NLRP3 activation (123). Studies have shown that Syk participates in the activation of the Syk/JNK/NLRP3 signaling pathway in high-glucose-induced HK2 cells and rat glomerular mesangial cells, mediating glomerular hypertrophy and mesangial expansion in diabetic rats. Furthermore, Syk can induce apoptosis in HK2 cells. JNK activation translocates into the nucleus, where it alters AP-1 transcription and expression through posttranscriptional mechanisms, potentially leading to insulin resistance (IR), insulin deficiency, hyperglycemia, and a high-glucose-mediated inflammatory cycle, thereby exacerbating the progression of DN. ERK1/2 can also phosphorylate intracellular PLA2, releasing arachidonic acid and eicosanoids, thereby altering renal hemodynamics in DN. Additionally, ERK1/2 can promote mesangial cell proliferation and glomerulonephritis via PKC and PTK, accelerating the progression of DN (124). Literature reports indicate that activation of p38MAPK is essential for NLRP3-mediated IL-1 secretion and plays a critical role in the secretion of IL-1β and IL-18 (125). When activated by the inflammasome, p38MAPK enhances the binding capacity of activator protein-1 (AP-1) and increases TGF-β gene expression, thereby positively regulating p38MAPK signaling through a feedback loop. Consequently, when this pathway is activated and TGF-β is overexpressed, a vicious cycle ensues, promoting mesangial cell proliferation and extracellular matrix accumulation.

Tubulointerstitial fibrosis is one of the primary causes of DN, with multiple contributing factors, including heavy proteinuria, epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, and interstitial cell infiltration. Wallys Garrido et al. also found that caspase-1, IL-18, IL-6, IL-10, and the pro-fibrotic marker α-SMA were all upregulated, mediating renal injury and proteinuria (126). Kehong Chen et al. discovered in DN renal tubular epithelial cells that the expression of optineurin (OPTN) was negatively correlated with NLRP3 inflammasome activation, which mediated renal interstitial inflammation (127). Overexpression of OPTN promoted mitophagy, thereby inhibiting NLRP3 inflammasome activation. Wenbei Han et al. demonstrated in a rat model of DN that inflammasome activation and TLR4/NF-κB signaling mediated the transdifferentiation of renal tubular epithelial cells (128). Chenxu Ge et al. observed significant insulin resistance and glucose intolerance in an obese animal model, accompanied by renal inflammation and increased expression of IL-1β, IL-18, TNF-α, and IL-6, potentially mediated by NF-κB/NLRP3 signaling, which was further validated in human immortalized renal tubular epithelial cells (129). IncRNA-GM4419 can activate the NF-κB pathway by directly interacting with the p50 subunit of NF-κB, and p50 can also directly interact with the NLRP3 inflammasome (130). Wei Li et al. found that total astragalus extract (TEA) reduced doxorubicin-induced morphological changes, viability loss, and cell death in renal tubular epithelial cells by inhibiting the ROS-ERK1/2-NLRP3 inflammasome axis, strongly indicating that the NLRP3 inflammasome plays a critical role in tubular damage and interstitial fibrosis in DN (131).

Current clinical management of diabetic nephropathy (DN) remains anchored in the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) to inhibit the renin–angiotensin–aldosterone system (RAAS). Although these agents effectively delay disease progression, they are incapable of reversing or eliminating established renal injury (132). Consequently, a rapidly expanding body of research has centered on the NLRP3 inflammasome as a pivotal therapeutic node, seeking to identify interventions that may not only halt but potentially reverse DN by targeting upstream activators and downstream effectors of inflammasome signaling. Targeting the NF-κB signaling pathway: Multiple pharmacological agents have been identified that mitigate renal injury in diabetic nephropathy through suppression of NF-κB signaling. Liquiritigenin alleviates high glucose (HG)-induced extracellular matrix accumulation, oxidative stress, and inflammation by concurrently inhibiting NF-κB and NLRP3 inflammasome pathways (132). The Huangkui capsule reduces tubular epithelial-to-mesenchymal transition (EMT) via blockade of the TLR4/NF-κB signaling axis (128). The insulin-sensitizing agent pioglitazone downregulates the expression of advanced glycation end products (AGEs), their receptor RAGE, and NF-κB, thereby suppressing NLRP3 activation and downstream pro-inflammatory mediators. Fisetin (FIS) inhibits NF-κB activation and ameliorates insulin resistance by targeting receptor-interacting protein kinase 3 (RIP3)-mediated inflammatory signaling (129). Pharmacological blockade of adenosine A3 receptors reduces nuclear translocation of NF-κB and attenuates caspase-1 activation in renal tubular epithelial cells of diabetic rats (126). Thrombomodulin domain 1 (THBD1) protects against DN-associated renal injury by suppressing NF-κB/NLRP3 activation, dampening Nrf2 activity, and reducing podocyte autophagy (133). These findings collectively highlight NF-κB as a master regulatory node whose targeted inhibition may serve as a powerful indirect strategy to suppress NLRP3 inflammasome activation.

Through the inhibition of ROS generation, apocynin, an anti-inflammatory compound, suppresses ROS production and thereby attenuates NLRP3 activation. In DN rat models, apocynin intervention correlates with reduced expression of the X-linked inhibitor of apoptosis protein (XIAP), which parallels decreased NLRP3 levels—suggesting that XIAP may participate in ROS-mediated NLRP3 inflammasome activation (134). The redox-sensitive transcription factor Nrf2 serves as a central endogenous regulator of ROS homeostasis; minocycline and curcumin exert renoprotective effects, at least in part, by modulating Nrf2 activity (101, 135). Multiple herbal extracts, including luteolin (136), curcumin, crocin, cinnamon, and garlic extracts, inhibit NLRP3 inflammasome activation by suppressing ROS generation, mitigating oxidative stress, or enhancing insulin sensitivity (137). Rapamycin activates autophagy, reduces ROS accumulation, and protects podocytes. Optineurin suppresses NLRP3 activation by enhancing mitophagy and reducing mitochondrial ROS (mtROS) production (127). Total extract of astragalus (TEA) inhibits NLRP3 activation by blocking ERK1/2 signaling within the ROS–ERK1/2–NLRP3 axis (57). Current research on ROS inhibitors remains heavily focused on traditional herbal compounds; rigorous mechanistic dissection and comprehensive pharmacotoxicological profiling are essential to accelerating their clinical translation. Targeting NLRP3 inflammasome activity: Minocycline attenuates NLRP3 inflammasome activation by silencing NLRP3 or ASC gene expression or by inhibiting caspase-1 activity. Silencing of TXNIP enhances the expression of antioxidant factors and suppresses high glucose-induced NLRP3 inflammasome activation and podocyte injury (138). Glibenclamide, verapamil, and salidroside inhibit HG-induced TXNIP upregulation and subsequent NLRP3 inflammasome assembly (57, 139). Genetic ablation of NLRP3 reduces the expression of TXNIP and NADPH oxidase 4 (NOX4), enhances superoxide dismutase (SOD) production, and attenuates IL-1β and IL-18 expression (140). NLRP3 silencing (141) further suppresses ROS generation and TGF-β1-induced EMT in renal tubular epithelial cells, restores podocyte autophagy, and ameliorates HG-induced podocyte damage. Li Fang et al. (120) demonstrated that tauroursodeoxycholic acid (TUDCA) enhances endoplasmic reticulum (ER) stress adaptation and reduces NLRP3 activation triggered by proteinuria in DN. MCC950, a highly selective NLRP3 inhibitor, specifically blocks caspase-1-dependent NLRP3 activation and IL-1β secretion without interfering with TLR signaling or the priming phase of inflammasome assembly (142); it improves renal function, reduces mesangial expansion and basement membrane fibrosis, and attenuates tubular dilation—effects achieved independently of changes in body weight or glycemia (143). IL-22 inhibits NLRP3 activation, reduces albuminuria, and attenuates renal fibrosis (144). Genetic deletion of TLR4 mitigates HG-induced podocyte injury and renal damage via suppression of the NLRP3 inflammasome (145). In macrophages, regulated in development and DNA damage response 1 (REDD1), which is partially localized to mitochondria, promotes NLRP3 activation via ROS generation and potentially through NF-κB-dependent mechanisms. Faustine Pasto et al. showed that REDD1 deficiency in macrophages cocultured with adipocytes reduces NLRP3 expression, IL-1β secretion, and insulin resistance (146). Collectively, inhibition of NLRP3 inflammasome activation significantly attenuates renal tissue damage and partially restores renal function; however, clinically viable, tissue-specific NLRP3-targeted therapeutics remain scarce and urgently require further development.

Downstream of inflammasome activation, direct targeting of effector cytokines—particularly IL-1β and IL-18—offers a complementary therapeutic approach. The U.S. Food and Drug Administration (FDA) has approved several IL-1β antagonists, including rilonacept, canakinumab, and anakinra, which reduce glycated hemoglobin levels, enhance insulin secretion, and suppress systemic inflammation in patients with type 2 diabetes, albeit with suboptimal pharmacokinetic profiles (147). Losartan also suppresses IL-1β expression and partially inhibits NLRP3 inflammasome activation (148). Dapagliflozin, an SGLT2 inhibitor, reduces systemic inflammation by lowering circulating levels of C-reactive protein, IL-6, and TNF-α (149). Ginsenoside compound K (CK) inhibits ROS-mediated NLRP3 activation and NF-κB/p38 MAPK signaling and exhibits synergistic effects with MCC950 and VX765 (a caspase-1 inhibitor) in suppressing the IL-1β concentration (150).

With the advancement of research both domestically and internationally, pyroptosis has been firmly established as a critical contributor to the initiation and progression of DKD. Here, we systematically summarize the key molecular components involved in pyroptotic signaling, including inflammasome assembly (notably the NLRP3 inflammasome), activation of the caspase family (particularly caspase-1/4/5/11), and the pore-forming activity of GSDMD. Nevertheless, our current understanding of how pyroptosis mechanistically drives DKD pathogenesis remains incomplete. The precise molecular events governing each step of pyroptotic execution, from inflammasome priming to membrane rupture, have not yet been fully elucidated. Moreover, the functional significance of pyroptosis-induced cell death in the context of DKD progression is still largely confined to preclinical models. Therefore, comprehensive and mechanistic investigations are urgently needed to delineate the specific roles and regulatory networks of pyroptosis and inflammasome activation in DKD—insights that may ultimately reveal novel therapeutic targets for this devastating complication of diabetes.

An expanding body of evidence demonstrates that the NLRP3 inflammasome contributes to the pathogenesis of multiple kidney diseases, including IgA nephropathy (154, 158). In patients with IgA nephropathy, circulating levels of NLRP3 inflammasome-derived cytokines, notably interleukin-18 (IL-18) and interleukin-1β (IL-1β), are significantly elevated (154, 159), underscoring the inflammasome's central role in disease progression. Targeted inhibition of NLRP3 within the kidney has therefore emerged as a promising therapeutic strategy for IgA nephropathy (156). Further mechanistic insights reveal that colorectal neoplasia differentially expressed (CRNDE), a long non-coding RNA, exacerbates IgA nephropathy by promoting NLRP3 inflammasome activation in macrophages; conversely, CRNDE suppression enhances NLRP3 degradation, thereby attenuating renal inflammation (155). Clinically, peripheral blood mononuclear cells from IgA nephropathy patients exhibit elevated NLRP3 mRNA expression, which correlates positively with renal fibrosis indices (160). Moreover, serum exosomes from these patients show markedly increased NLRP3 levels, which correlate positively with proteinuria severity and Katafuchi histological scores and negatively with the estimated glomerular filtration rate (eGFR). Importantly, NLRP3 inflammasome expression within renal tissue is significantly upregulated and strongly correlates with its levels in circulating exosomes (161). Within the tubulointerstitium of IgA nephropathy kidneys, the expression of the NLRP3 inflammasome, IL-18, and monocyte chemoattractant protein-1 (MCP-1) is markedly increased and positively correlates with the degree of proteinuria, tubular atrophy, interstitial inflammatory cell infiltration, and fibrosis (162). The activation of the NLRP3 inflammasome in IgA nephropathy is orchestrated through multiple interconnected pathways—including NF-κB signaling, impaired autophagy, mitochondrial reactive oxygen species (mtROS) overproduction, and exosome-mediated intercellular communication (154). Critically, injury or dysfunction of intrinsic renal cells, including podocytes, mesangial cells, glomerular endothelial cells, and tubular epithelial cells, is closely linked to activation of the NLRP3 inflammasome.

Podocytes constitute the final filtration barrier of the glomerulus. Their injury—manifested ultrastructurally by foot process effacement and detachment, and histologically by hypertrophy, focal sclerosis, Bowman's capsule adhesion, and podocyte loss—represents a hallmark lesion in IgA nephropathy and a key driver of proteinuria and progressive renal decline (163 –165). Podocyte injury is now widely recognized as a central mechanism underlying disease progression in IgA nephropathy (163, 164). Emerging evidence indicates that IgA1-containing immune complexes directly trigger NLRP3 inflammasome activation in both macrophages and podocytes in IgA nephropathy (159). Compared with healthy controls, renal tissue from IgA nephropathy patients exhibits significantly elevated NLRP3 inflammasome expression. Notably, co-localization of NLRP3 with the macrophage marker F4/80 is detectable within podocytes, suggesting phenotypic transition. Patients with an estimated glomerular filtration rate (eGFR) < 60 mL·min⁻¹·(1.73 m²)⁻¹ show markedly increased tubular NLRP3 expression, whereas those with heavy proteinuria (≥3.5 g·day⁻¹) exhibit significantly elevated glomerular NLRP3 levels. Critically, aberrantly glycosylated IgA1 isolated from the serum of IgA nephropathy patients induces NLRP3 expression in cultured podocytes and upregulates F4/80—a macrophage lineage marker—concomitant with increased expression of the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) and the fibrotic marker α-smooth muscle actin (α-SMA). These findings indicate that pathogenic IgA1 not only activates the NLRP3 inflammasome in podocytes but also initiates podocyte-to-macrophage transdifferentiation (PMT). Following PMT, these transformed podocytes secrete pro-inflammatory cytokines that amplify inflammatory cascades and promote renal fibrosis—key pathological features of IgA nephropathy (158).

Mesangial cells reside between glomerular capillaries, embedded within the mesangial matrix. They maintain direct contact with endothelial cells and intimate crosstalk with podocytes, collectively forming the functional architecture of the glomerulus. Disruption of mesangial cell homeostasis, whether by immune complexes, hemodynamic stress, or metabolic insults, triggers their pathological activation. This activation drives mesangial cell proliferation and hypertrophy, expansion of the extracellular matrix, release of pro-inflammatory mediators, and complement activation, ultimately culminating in mesangiolysis and loss of glomerular capillary loops, thereby impairing glomerular filtration (166). In IgA nephropathy, aberrant deposition of IgA within the mesangium serves as a potent trigger for NLRP3 inflammasome activation, initiating a cascade of localized inflammation that promotes mesangial cell hyperproliferation and excessive extracellular matrix accumulation—key histopathological features driving progressive glomerular injury. This IgA–NLRP3 axis is now widely regarded as a central pathogenic mechanism in IgA nephropathy. Tripartite motif (TRIM) proteins, a family of E3 ubiquitin ligases, play critical regulatory roles in innate immunity. Using an in vitro model of human glomerular mesangial cells (GMCs) stimulated with pathogenic IgA1, researchers demonstrated that IgA1 promotes GMC proliferation via NLRP3 inflammasome activation. Notably, TRIM40 suppresses IgA1-induced GMC proliferation by inhibiting NLRP3 inflammasome assembly and downstream signaling (167). Furthermore, in a cellular model of IgA nephropathy established by culturing human renal tubular epithelial cells (HK-2 cells) with conditioned medium from IgA-stimulated human mesangial cells (HMCs), NLRP3 mRNA and protein expressions were significantly upregulated in HK-2 cells, accompanied by increased levels of ASC and caspase-1-indicating that mesangial-derived inflammatory signals can propagate NLRP3 activation to tubular compartments, thereby linking glomerular injury to tubulointerstitial inflammation (168).

Clinical studies consistently report that endothelial damage, often accompanied by endothelial cell loss, is a hallmark histopathological feature of IgA nephropathy (169). In acute glomerular lesions of IgA nephropathy, endothelial cell proliferation, fibrinoid necrosis, and the presence of cellular or fibrocellular crescents are strongly associated with hematuria, with or without concurrent proteinuria. In chronic lesions, segmental or global glomerulosclerosis correlates significantly with the severity of proteinuria and elevated serum creatinine levels. Collectively, injury to glomerular capillaries and loss of endothelial integrity in both acute and chronic phases of IgA nephropathy are thought to directly contribute to hematuria, proteinuria, and progressive renal dysfunction (169). In animal models of IgA nephropathy, ultrastructural abnormalities such as endothelial vacuolization and mesangial interposition have been observed, further supporting the role of endothelial injury in disease progression (170). Galactose-deficient IgA1 (Gd-IgA1) immune complexes exhibit high affinity for glomerular endothelial cells. Their deposition triggers glycocalyx shedding and disrupts the glomerular filtration barrier. Moreover, Gd-IgA1 complexes accelerate the production of adhesion molecules and pro-inflammatory cytokines in endothelial cells. This endothelial damage, induced by Gd-IgA1 deposition, may enhance the permeability of mesangial regions to immunoglobulins and amplify subsequent inflammatory responses—thereby potentiating core pathogenic mechanisms in IgA nephropathy (171). In vitro models using human glomerular endothelial cells exposed to high glucose demonstrate robust activation of the NLRP3 inflammasome, accompanied by excessive secretion of IL-18 and IL-1β—suggesting that metabolic stress synergizes with immune injury to exacerbate endothelial dysfunction via inflammasome signaling (172). Notably, retinoic acid receptor responder 1 (Rarres1) is detectably expressed in glomerular and peritubular capillary endothelial cells in IgA nephropathy and related glomerulopathies. Induction of Rarres1 in endothelial cells represents a conserved molecular mechanism that drives inflammation and fibrosis through activation of the NF-κB signaling pathway (173).

In IgA nephropathy, injury to renal tubular epithelial cells primarily arises from glomerular filtration barrier dysfunction and pathological crosstalk between mesangial and tubular compartments. Filtered proteins, including albumin (ALB), complement components, cytokines, growth factors, and galactose-deficient IgA1 (Gd-IgA1), play pivotal roles in driving tubulointerstitial damage. These filtered molecules stimulate proximal tubular epithelial cells to secrete a spectrum of inflammatory mediators, thereby establishing a pro-inflammatory microenvironment within the tubulointerstitium (174). Crosstalk between mesangial cells and tubular epithelial cells is mediated by key signaling molecules, including TNF-α, TGF-β1, and MCP-1 (175). NLRP3 is expressed in human kidney biopsy specimens and in primary human proximal tubular cells (HPTCs), and its expression levels correlate with clinical outcomes in IgA nephropathy. In healthy human kidneys, NLRP3 is predominantly localized to renal tubules and, within human proximal tubular cells (HPTCs), to mitochondria. Compared with control kidneys, renal tissues from patients with IgA nephropathy exhibit significantly elevated NLRP3 gene expression. Although NLRP3 protein can be detected in glomeruli, its expression is primarily confined to the tubular epithelial compartment. In vitro, stimulation of HPTCs with TGF-β1 transiently induces NLRP3 mRNA and protein expression. However, over time, these cells undergo phenotypic transition, losing their epithelial identity through transcriptional reprogramming and ubiquitin-mediated degradation, which coincides with progressive downregulation of NLRP3 expression. Consistent with these in vitro findings, low NLRP3 mRNA expression in renal biopsies correlates with a linearly increased risk of the composite endpoint of serum creatinine doubling and progression to end-stage kidney disease in IgA nephropathy patients (176). Collectively, these data indicate that NLRP3 is predominantly a tubule-expressed protein in the human kidney, and its expression is paradoxically reduced in progressive IgA nephropathy.

Tripterygium wilfordii (Lei Gong Teng) is widely used in the treatment of inflammatory and autoimmune diseases. Extensive clinical, animal, and in vitro studies confirm its potent anti-inflammatory effects (177, 178). Mechanistically, Tripterygium and its bioactive constituents modulate immune cell function and suppress expression of cytokines, adhesion molecules, and inflammatory mediators through multiple signaling pathways—including NF-κB, MAPK, STAT, NLRP3 inflammasome, and Wnt (179). Diterpenoids 1 and 6 isolated from Tripterygium inhibit LPS-induced inflammation in murine macrophages by suppressing MAPK and NF-κB signaling and STAT3 activation, thereby reducing NLRP3 inflammasome assembly and expression of inflammatory mediators such as COX-2, iNOS, IL-6, IL-1β, and IL-18 (180). Triptolide, a principal bioactive diterpenoid epoxide from Tripterygium, exhibits the strongest anti-inflammatory and immunosuppressive activity among its constituents (181). In IgA nephropathy rat models, triptolide significantly reduces serum creatinine (SCr), blood urea nitrogen (BUN), and 24-h urinary protein excretion. It also lowers serum levels of TNF-α, IL-17A, interferon-γ (IFN-γ), and IL-4, attenuates renal IgA deposition, and suppresses renal expression of IL-1β, caspase-1, IL-18, and NLRP3—suggesting its renoprotective effects are mediated, at least in part, through inhibition of NLRP3 inflammasome activation (182). Triptolide's anti-inflammatory action is further linked to suppression of the NLRP3/TLR4 axis, reducing IL-1β and IL-18 levels, limiting immune complex deposition and mesangial proliferation, and ameliorating proteinuria (183). Celastrol, a quinone methide triterpenoid extracted from Tripterygium root bark, possesses anti-inflammatory, immunosuppressive, and antitumor activities (184). It inhibits NF-κB signaling, downregulates NLRP3 expression, and blocks caspase-1 cleavage, thereby suppressing IL-1β and IL-18 production in LPS-stimulated macrophages (185). In IgA nephropathy models, celastrol attenuates hematuria and proteinuria by inhibiting the Notch signaling pathway in renal tissue (186). Wogonoside alleviates mesangial cell proliferation and matrix expansion in IgA nephropathy rats. It elevates cytoplasmic NF-κB levels while reducing nuclear NF-κB translocation and dose-dependently lowers SCr, BUN, IL-1β, TNF-α, 24-h urinary protein, and red blood cell counts. It also suppresses the renal expression of nuclear NF-κB, nuclear/total NF-κB ratio, NLRP3, ASC, pro-caspase-1, and caspase-1 (187). Baicalin reduces BUN, SCr, and 24-h urinary protein in rats with mesangial proliferative glomerulonephritis. It decreases the kidney-to-body weight ratio, glomerular apoptosis rate, and renal mRNA and protein levels of NLRP3 and caspase-1 (43, 188). Plumbagin significantly reduces urinary protein, SCr, and BUN in IgA nephropathy rats. It attenuates renal oxidative stress by lowering ROS and malondialdehyde (MDA) levels while enhancing superoxide dismutase (SOD) activity. Plumbagin also reduces serum MDA, IL-1β, IL-18, and TNF-α and downregulates renal expression of NLRP3, ASC, caspase-1, PI3K, Akt, and NF-κB (49, 189). In a separate study, plumbagin suppressed apoptosis and oxidative stress in renal tissue, reduced pro-IL-1β and pro-IL-18 levels, and inhibited NLRP3/ASC/caspase-1 protein expression (190). It also inhibits proliferation of human mesangial cells and downregulates the expression of TGF-β1, CTGF, and fibronectin (FN) (191). Geniposide dose-dependently reduces 24-h urinary protein, BUN, and SCr in IgA nephropathy mice. It attenuates IgA deposition, mesangial expansion, and inflammatory cell infiltration, while suppressing renal oxidative stress and inflammation. Geniposide significantly reduces renal NLRP3 protein expression. Notably, NLRP3 knockout (KO) mice exhibit similar protective effects as geniposide treatment (100 mg/kg), whereas geniposide shows no additional benefit in NLRP3 KO mice—strongly implicating NLRP3 as its primary molecular target (192). Icariin, a flavonoid from epimedium, reduces urinary red blood cells, proteinuria, and urinary N-acetyl-β-D-glucosaminidase (NAG) in experimental IgA nephropathy rats. It diminishes renal IgA deposition and suppresses renal protein expression of NF-κB p65 and MCP-1, as well as mRNA levels of IL-4, IL-10, and IL-13 (193). Icariin also lowers serum IL-1β, IL-6, and IL-18, reduces renal expression of TGF-β1, collagen IV (Col IV), and FN1, and inhibits nuclear translocation of NF-κB p65, TNF-α, and VCAM-1 (194). Its renoprotective mechanism involves blockade of NF-κB nuclear translocation and NLRP3 inflammasome activation, thereby reducing downstream pro-inflammatory cytokine production (195). Artemisinin, derived from Artemisia annua, alleviates renal injury in IgA nephropathy mice. Network pharmacology and molecular docking analyses, validated experimentally, suggest that artemisinin activates the Akt/Nrf2 signaling pathway to exert therapeutic effects (196). Artemisinin significantly reduces 24-h urinary protein and hematuria, lowers serum creatinine, BUN, total cholesterol, and triglycerides, while increasing serum albumin and total protein. It suppresses renal production of IL-4 and IL-17, ameliorates glomerular mesangial matrix expansion and cell proliferation, and protects renal structure. Mechanistically, artemisinin enhances exosome secretion, which in turn inhibits NF-κB/NLRP3 inflammasome activation (197). When combined with hydroxychloroquine, artemisinin further amplifies exosome release from tubular epithelial cells; upon uptake by mesangial cells, these exosomes suppress NF-κB signaling and NLRP3 inflammasome activity, downregulating the expression of IκBα, p-p65, NLRP3, ASC, IL-1β, and caspase-1, ultimately attenuating renal inflammation (197). Emerging evidence indicates that ROS generation, coupled with activation of NF-κB and the NLRP3 inflammasome, constitutes a central pathogenic axis driving the progression of IgA nephropathy (198). In murine models of IgA nephropathy, treatment with osthole, a bioactive coumarin derivative, confers significant renoprotection: It prevents proteinuria, improves renal function, and halts progressive histopathological lesions, including glomerular hypercellularity, glomerulosclerosis, and periglomerular monocyte infiltration. Mechanistically, osthole reduces renal superoxide anion levels and promotes nuclear translocation of the antioxidant transcription factor Nrf2. It concurrently suppresses activation of NF-κB and the NLRP3 inflammasome in renal tissue, leading to decreased expression of MCP-1 and reduced monocyte infiltration. In vitro, osthole inhibits ROS production and NLRP3 inflammasome activation in stimulated macrophages. In activated mesangial cells, it similarly attenuates ROS generation and downregulates MCP-1 protein expression. Collectively, these findings demonstrate that osthole exerts its therapeutic effects in IgA nephropathy primarily by targeting renal oxidative stress and interrupting the ROS–NF-κB–NLRP3 inflammatory cascade—positioning it as a promising multi-target natural agent for disease modification.

Under physiological conditions, inflammatory responses serve to eliminate pathogens and promote tissue repair. However, dysregulated or excessive inflammation can inflict significant tissue damage. Although the NLRP3 inflammasome, a key component of the innate immune system, plays a critical role in host defense against infection, its hyperactivation contributes to the pathogenesis of multiple autoimmune diseases, including LN. Clinical evidence demonstrates that the expression levels of NLRP3 and caspase-1 are significantly elevated in renal biopsies from LN patients (202). Moreover, NLRP3 mRNA levels are markedly upregulated in LN kidney tissue and inversely correlate with renal function (71). These clinical observations are further supported by robust experimental data from murine lupus models. In (NZB×NZW)F1 lupus-prone mice, renal NLRP3 inflammasome activation is markedly enhanced (203). Zhao et al. confirmed pronounced upregulation of the NLRP3 inflammasome in the kidneys of MRL/lpr mice; notably, pharmacological or genetic inhibition of NLRP3 attenuates disease severity in this model (204). Conversely, forced overexpression of NLRP3 exacerbates end-organ damage in lupus mice, underscoring its pathogenic role in LN progression (205). Earlier work from our group demonstrated that pharmacological inhibition of pro-caspase-1 activation reduces IL-18 production, subsequently dampening IFN-γ secretion, and confers significant protection in murine LN models (206). Kahlenberg et al. were the first to employ genetic knockout models to dissect inflammasome function in lupus. Compared with wild-type mice, caspase-1⁻/⁻ lupus mice exhibit significantly reduced serum titers of anti-dsDNA antibodies and anti-ribonucleoprotein antibodies, along with attenuated type I interferon responses, thereby decreasing immune complex formation and subsequent renal damage (207). This suggests that caspase-1 is involved in the pathogenesis of LN. The pathogenic roles of NLRP3-derived cytokines IL-1β and IL-18 in SLE have long been established in preclinical models (208 –210). Our earlier studies further revealed that plasma and renal IL-18 levels positively correlate with proteinuria, histopathological damage, and IgG immune complex deposition in BXSB lupus mice—suggesting that elevated IL-18 may directly contribute to glomerular filtration barrier disruption and autoimmune renal injury in LN (211). Interleukin-18 binding protein (IL-18BP), the endogenous high-affinity antagonist of IL-18, is significantly upregulated in both renal tissue and peripheral blood of LN patients. Importantly, an imbalance between IL-18 and IL-18BP may actively contribute to lupus pathogenesis (212, 213). Recent clinical studies corroborate these findings, reporting significantly elevated serum levels of IL-1β and IL-18 in SLE patients—highlighting the clinical relevance of inflammasome-derived cytokines in disease progression (214, 215). Intriguingly, loss of NLRP3 function has also been linked to autoimmune dysregulation. Sester et al. serendipitously discovered a spontaneous NLRP3 mutation in NZB mice (216). This mutation may alter host–microbiome interactions and promote the generation of autoreactive antibodies. More directly, Lech et al. demonstrated that genetic deletion of NLRP3 or ASC in lupus-prone mice leads to hyperactivation of dendritic cells and macrophages, excessive production of pro-inflammatory mediators, and accelerated T- and B-cell proliferation (217). Mechanistically, NLRP3 and ASC deficiency strongly suppresses TGF-β receptor-mediated immunosuppressive signaling. Collectively, these findings reveal a paradoxical duality of the NLRP3 inflammasome in autoimmunity: Basal, homeostatic NLRP3 activity may be essential for immune tolerance and suppression of aberrant lymphocyte activation; however, sustained or excessive NLRP3 inflammasome activation drives cytokine storm, immune dysregulation, and target organ damage—thereby fueling LN progression. This delicate balance must be carefully considered in the development of NLRP3-targeted therapies for LN: Complete inhibition may risk unleashing compensatory hyperinflammation, whereas selective or context-dependent modulation may offer optimal therapeutic benefit.

The evidence outlined above establishes that core components of the NLRP3 inflammasome—including NLRP3, ASC, and caspase-1—are critically involved in the pathogenesis of LN. Below, we delineate how activated NLRP3 inflammasome signaling drives renal injury by modulating both circulating immune cells and intrinsic renal cells. A central mechanism involves the NLRP3 inflammasome's regulation of CD4⁺ T-cell differentiation—particularly the Th1 and Th17 subsets, which are key drivers of renal inflammation in LN. The inflammasome promotes Th1 and Th17 polarization primarily through caspase-1–dependent secretion of IL-1β and IL-18. In both human and murine systems, IL-1β—in synergy with TGF-β—induced the expression of the transcription factors IRF4 and RORγt, thereby promoting the differentiation of naïve CD4 T cells into pathogenic Th17 cells. Conversely, IL-18 acting in concert with IL-12 drives naïve CD4 T cells toward a Th1 fate characterized by IFN-γ production. Notably, IL-18 itself is also secreted by Th1 cells, creating a self-amplifying inflammatory loop. In experimental autoimmune encephalomyelitis (EAE), a Th1/Th17-driven model, genetic ablation of NLRP3 significantly attenuates disease severity by dampening Th1- and Th17-mediated immune responses. Further mechanistic insight comes from studies of ASC-deficient CD4 T cells, which paradoxically secrete elevated levels of the immunoregulatory cytokine IL-10. This IL-10 surge suppresses proliferation of neighboring T cells and inhibits their production of IFN-γ and IL-2, highlighting a cell-intrinsic immunosuppressive function of ASC in T cells (218).

Activation of the NLRP3 inflammasome also critically contributes to the pathogenesis of LN by modulating the function of macrophages and dendritic cells. Infiltrating renal macrophages exacerbate glomerular injury and tubulointerstitial inflammation through the secretion of IL-1β and IL-18. In SLE, abundant neutrophil extracellular traps (NETs) are released into the circulation. These NETs directly activate the NLRP3 inflammasome in both human and murine macrophages, triggering robust IL-1β and IL-18 secretion. In turn, IL-18 stimulates neutrophils to generate additional NETs—establishing a self-amplifying positive feedback loop that accelerates systemic inflammation in SLE (216). During SLE flares, cell death releases double-stranded DNA (dsDNA), which, together with subsequently generated anti-dsDNA autoantibodies, engages TLR4 on monocytes and macrophages. This interaction induces ROS production and potassium efflux, both of which serve as canonical triggers for NLRP3 inflammasome assembly. Notably, pharmacological antioxidants or genetic downregulation of TLR4 significantly suppresses NLRP3 activation in these myeloid cells (219). More recently, it has been demonstrated that reduced serum high-density lipoprotein (HDL) levels in SLE patients impair cholesterol efflux in dendritic cells. This lipid dysregulation activates the NLRP3 inflammasome, enhancing secretion of pro-inflammatory cytokines and promoting polarization of CD4⁺ T cells toward Th1 and Th17 phenotypes. Crucially, knockdown of NLRP3 expression in dendritic cells markedly attenuates these inflammatory and immunomodulatory effects, underscoring the central role of NLRP3 in bridging lipid metabolism, innate immunity, and adaptive T-cell responses in SLE (220).

It has been firmly established through both in vivo and in vitro studies that intrinsic renal cells in humans and rodents, including podocytes (221 –223), mesangial cells (121, 224), glomerular endothelial cells (68), and tubular epithelial cells (225, 226), are capable of expressing the NLRP3 inflammasome. Upon activation, these cells cleave pro-caspase-1 into its active form, leading to the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18—thereby directly contributing to local renal inflammation and tissue injury. Below, we focus on the impact of NLRP3 inflammasome activation in tubular epithelial cells and podocytes, two key cellular compartments in LN. Tubulointerstitial inflammation is a critical determinant of disease progression in LN. Upon injury, damaged or necrotic tubular epithelial cells release DAMPs—including ROS, extracellular ATP, uric acid, nucleic acids, and extracellular matrix components (e.g., hyaluronan, biglycan). These DAMPs activate the NLRP3 inflammasome within neighboring tubular epithelial cells, triggering the release of inflammatory cytokines and chemokines that recruit neutrophils, macrophages, natural killer cells, and lymphocytes into the renal interstitium. This cascade amplifies local inflammation and accelerates tubulointerstitial injury (227). Our previous work demonstrated that elevated IL-18 expression in tubular epithelial cells correlates strongly with the severity of tubulointerstitial damage in LN (228). Faust et al. further confirmed that upregulation of IL-18 in renal tubules positively correlates with histological and functional kidney injury in murine LN models (229, 230). In LN, anti-dsDNA autoantibodies can bind directly to tubular epithelial cells, promoting tubulointerstitial inflammation, a process likely mediated, at least in part, by NLRP3 inflammasome activation. Moreover, NLRP3 signaling in tubular cells not only drives inflammation but also contributes to tissue repair and, paradoxically, to maladaptive fibrogenesis (231). Thus, the NLRP3 inflammasome in tubular epithelial cells is intimately linked to both the inflammatory and fibrotic phases of tubulointerstitial injury in LN. Podocytes are essential for maintaining the structural and functional integrity of the glomerular filtration barrier—and are consistently targeted in LN. Zhang et al. first demonstrated in a hyperhomocysteinemia model that NLRP3 inflammasome activation in podocytes induces foot process effacement, contributing to glomerulosclerosis and proteinuria (221). Shahzad et al. further showed that NLRP3 activation in glomerular intrinsic cells (particularly podocytes) exacerbates glomerular injury in murine models of diabetic nephropathy, highlighting a conserved pathogenic role across glomerulopathies (231). In the context of SLE and LN, recent groundbreaking work from Prof. Niansheng Yang's team revealed that podocyte NLRP3 is activated by ROS in both LN patients and murine models. Critically, this activation directly mediates podocyte injury and contributes to disease pathogenesis—underscoring the indispensable role of podocyte-intrinsic NLRP3 signaling in LN progression (67).

As outlined above, the NLRP3 inflammasome plays a pivotal role in the pathogenesis of LN, offering novel avenues for targeted therapeutic intervention. Numerous studies have explored pharmacological agents capable of suppressing NLRP3 inflammasome activation, including inhibitors of its assembly and regulators of IL-1β and IL-18 secretion; however, most of these agents lack specificity for the NLRP3 pathway. Recently, however, two highly selective inhibitors targeting the NLRP3–ASC–caspase-1–IL-1β/IL-18 axis have emerged, holding significant promise for treating NLRP3-driven diseases, including LN and other autoimmune conditions. β-Hydroxybutyrate (BHB), a ketone body produced during fasting or caloric restriction, directly inhibits NLRP3 inflammasome activation by blocking potassium efflux and ASC oligomerization. Notably, BHB's inhibitory effect is independent of its chirality and does not rely on classical starvation-associated pathways—including AMPK signaling, ROS modulation, autophagy, or glycolysis inhibition. In both murine and human macrophage models, BHB significantly reduces LPS-induced secretion of IL-1β and other inflammatory cytokines. In NLRP3-dependent murine disease models, including Muckle–Wells syndrome, familial cold autoinflammatory syndrome, and monosodium urate crystal-induced peritonitis, BHB consistently suppresses caspase-1 activation and IL-1β release, confirming its broad anti-inflammatory efficacy (232). MCC950 is a small-molecule inhibitor that selectively blocks both canonical and non-canonical NLRP3 inflammasome activation, without affecting AIM2, NLRC4, or NLRP1 inflammasomes (142). In preclinical models, MCC950 reduces systemic IL-1β levels and ameliorates disease severity in experimental autoimmune encephalomyelitis. Critically, in the NZM2328 murine model of LN, MCC950 treatment significantly attenuates podocyte foot process effacement, improves renal histopathology, and reduces proteinuria—providing direct evidence of its renoprotective potential in lupus nephritis (47). Accumulating evidence underscores the indispensable role of the NLRP3 inflammasome in LN pathogenesis. DAMPs generated during immune dysregulation activate NLRP3 in both circulating immune cells and intrinsic renal cells, leading to caspase-1–dependent maturation and secretion of IL-1β and IL-18. Despite extensive research, the precise molecular mechanisms by which NLRP3 contributes to LN progression remain incompletely defined, necessitating further mechanistic and clinical investigations. While the development of pathway-specific inhibitors, such as BHB and MCC950, offers exciting therapeutic potential, their efficacy and safety in human LN patients remain to be rigorously validated in clinical trials. Translating these preclinical successes into clinical reality will require sustained, multidisciplinary efforts. In summary, as our understanding of the NLRP3 inflammasome in LN continues to deepen, it will pave the way for novel, mechanism-based therapies, not only for LN but also for a broad spectrum of NLRP3-driven autoimmune and inflammatory diseases.