The selective inhibition of the NLRP3 inflammasome by dapansutrile stems from its direct interaction with the NLRP3 protein, disrupting its assembly process. Structural insights from bioinformatics analyses reveal that dapansutrile anchors into the NACHT domain, which suppresses the domain’s ATPase function and thereby impedes the oligomerization of NLRP3 (Cao et al., 2022). This action effectively suppresses the formation of inflammasome specks, which are aggregates of components such as NEK7, NLRP3, and pro-IL-1β. (Kiran et al., 2022). In addition to directly binding NLRP3, Dapansutrile impedes inflammasome assembly through other binding mechanisms. By fluorescent resonance energy transfer (FRET) analysis, the researchers found that Dapansutrile reduced NLRP3 binding to ASC and Caspase-1. Importantly, dapansutrile exhibits high specificity for NLRP3 and does not influence the activation pathways of other inflammasomes, including AIM2 and NLRC4 (Marchetti et al., 2018a). This specificity may be due to the fact that Dapansutrile has no effect on the upstream signals that initiate inflammasomes, such as K+ efflux and P2X7 receptor. However, the effects of Dapansutrile on other NLRP family members or the pyrin inflammasome remain unclear. Here, we have also outlined the advantages and limitations of other NLRP3 inflammasome inhibitors currently under investigation.

Figure 2: Mechanism of Dapansutrile in NLRP3 Inflammasome Inhibition. NLRP3 inflammasome activation proceeds through two sequential stages: priming and activation. During the activation phase, Dapansutrile exerts its inhibitory effect by: (1) directly binding to the inactive NLRP3 protein, thereby preventing inflammasome assembly; and (2) reducing ROS production to suppress NLRP3 oligomerization. The figure was created in biorender.

Beyond direct NLRP3 inhibition, dapansutrile has been shown to modulate neutrophil chemotaxis. Studies indicate that it can interfere with the recruitment and activation of inflammatory cells. In a gouty arthritis model, dapansutrile alleviated local joint inflammation by reducing neutrophil infiltration to the site of inflammation (Marchetti et al., 2018b). This dual mechanism, simultaneously targeting inflammasome activation and immune cell migration, confers dapansutrile a unique therapeutic advantage in inflammatory diseases. Part of this activity may stem from its direct interaction with proinflammatory factors. A reported mechanism involves dapansutrile forming a stable complex with IL-1β, exerting a dual regulatory role in osteoblasts. It not only suppresses IL-1β–dependent pathways (evidenced by reduced COX2, iNOS, and MMP3) but also promotes the expression of anti-inflammatory and pro-regenerative mediators (IL-10, SOX9, COL2), thereby tilting the cellular balance toward repair (Tang et al., 2022). These findings suggest that dapansutrile modulates inflammation both directly at the cytokine level and indirectly through immune cell regulation. Additionally, besides neutrophils, dapansutrile can inhibit tissue infiltration by T cells and mast cells, thereby ameliorating disease severity in models such as interstitial cystitis (Kiran et al., 2022).

The anti-pyroptotic effect of dapansutrile represents another key anti-inflammatory mechanism. By suppressing NLRP3 inflammasome activation, it inhibits caspase-1–mediated cleavage of gasdermin D (GSDMD), ultimately preventing pyroptosis (Cai Y. et al., 2021). Pyroptosis is a programmed cell death mediated by GSDMD, which is characterized by the formation of plasma membrane pores and the release of inflammatory factors. Pyroptosis is necessary for the killing of bacteria and cancer cells. However, excessive pyroptosis leads to pathological activation of the inflammatory response (Bai et al., 2025). In an Alzheimer’s disease model, NLRP3-driven pyroptosis contributed significantly to disease progression, and dapansutrile ameliorated pathological changes via this pathway. Similarly, in a liver injury model, dapansutrile attenuated tissue damage by reducing ROS production and interrupting the ROS–NLRP3–pyroptosis axis (Fan et al., 2023). This anti-pyroptotic activity has been confirmed across multiple cell types, including microglia, airway epithelial cells, and hepatocytes (Zhang et al., 2024).

Dapansutrile also demonstrates notable synergistic effects when combined with other agents. For example, in a progeria model, co-administration with the farnesyltransferase inhibitor lonafarnib significantly improved inflammatory and aging phenotypes, extended survival, and alleviated progeria-like defects more effectively than lonafarnib alone (Muela-Zarzuela et al., 2024). Mechanistic studies suggest that this combination acts through concurrent inhibition of the NLRP3 inflammasome and protein farnesylation signaling. Notably, the two drugs jointly affect key inflammatory mediators such as HRAS, STAT3, JUN, and IL-6, forming a distinctive interaction network.

The complementary mechanisms of dapansutrile and other anti-inflammatory drugs support multi-level therapeutic synergism. For instance, its action complements that of p38 MAPK pathway inhibitors such as methotrexate (Alenezi et al., 2025). In the present study, dapansutrile similarly reduced the expression of inflammatory regulatory signals (CD4, CD8, IFN-γ, and JNK), although failed to completely restore them to normal levels. The regulation of inflammatory signaling by dapansutrile suggests potential combined applications with other anti-inflammatory molecules. Systems pharmacology analyses indicate that such combinations can produce enhanced anti-inflammatory outcomes by concurrently modulating processes like AKT phosphorylation and inflammasome activation. Metabolic pathway analyses further suggest that dapansutrile can complement the effects of glucocorticoids or NSAIDs through coordinated regulation of drug metabolism pathways (Dinarello et al., 2023). Specifically, dapansutrile inhibited the phosphorylation level of STAT3 Y705 as well as serine 727, thereby affecting the regulation of STAT3 on target genes as well as mitochondria. The combination of dapansutrile and dexamethasone reduced the ATP and glycolysis levels of the tumor cells, thus exerting a synergistic therapeutic effect. Overall, these combination strategies not only enhance therapeutic efficacy but may also allow dose reduction of individual drugs, thereby mitigating adverse effects.

To evaluate the concentration-dependent therapeutic efficacy of OLT1177, varying doses (60, 200, and 600 mg/kg) achieving plasma levels of 9.22 ± 0.55, 16.73 ± 9.89, and 41.4 ± 3.68 μg/mL, respectively, were administered in an MSU-induced gouty arthritis of murine model. The results established a direct correlation between the systemic exposure of OLT1177 and the magnitude of reduction in joint inflammation. Pretreatment with an OLT1177-enriched diet for 3 weeks prior to MSU challenge effectively suppressed the synovial expression of Nlrp3 and its downstream target Il1b. This molecular-level inhibition translated into a significant reduction in synovial IL-1β protein and, consequently, markedly less severe joint swelling compared to the standard diet group. These findings indicate that dapansutrile selectively inhibits the NLRP3 inflammasome, markedly alleviating joint swelling and improving motor dysfunction (Klück et al., 2020; Marchetti et al., 2018b). A phase 2a study enrolled 29 patients in the per-protocol population, with doses of 100, 300, 1000, and 2000 mg/day. Notably, plasma levels of IL-1β showed a decreasing trend across all groups, though statistical analysis revealed no intergroup differences. Significant reductions in plasma IL-6 concentrations were observed on day 7 in the 2000 mg/day, 1000 mg/day, and 300 mg/day groups (p < 0.05). In gout, elevated IL-6 levels may serve as a marker for active IL-1β, as the ability of IL-1β to induce IL-6 is well-established. Elevated IL-6 is commonly used as a surrogate marker for sub-picogram levels of IL-1β in humans. Concurrent with decreased IL-6 levels, most cohorts exhibited significant pain reduction in the target joint as early as day 3, with the 300 mg group demonstrating a mean pain reduction of 68.4% (p = 0.016). By day 7, all dose groups showed significant efficacy, with mean pain reduction rates ranging from 82.1% to 88.9% (Marchetti et al., 2018b).

Assessment of circulating cytokines during dapansutrile treatment revealed a distinct profile: a significant decline in plasma IL-6, no change in TNFα (an NLRP3-independent cytokine), and a non-significant reduction in IL-1β (Klück et al., 2020). The physiological relevance of monitoring IL-6 was further corroborated by a larger clinical study of 500 healthy volunteers, which demonstrated a strong correlation between plasma IL-6 and IL-1β levels, validating IL-6 as a proxy for IL-1β (Ter Horst et al., 2016). These results demonstrate that dapansutrile effectively alleviates target joint pain and local/systemic inflammation during acute gout flares, highlighting its potential as a novel NLRP3 inflammasome-targeted inhibitor for treating gout attacks and other NLRP3-mediated diseases.

Studies have shown that the NLRP3 inhibitor MCC950 significantly alleviates ligature-induced periodontitis, reduces IL-1β activation and osteoclast differentiation, and thereby inhibits alveolar bone resorption (He et al., 2020). Similarly, dapansutrile, via selective NLRP3 inflammasome inhibition, demonstrates potential in mitigating periodontitis-related bone loss (Marchetti et al., 2018a). Its mechanism involves multi-target regulation, including suppression of pro-inflammatory cytokines such as IL-1β and IL-6, as well as downregulation of matrix metalloproteinases including MMP3 (Tang et al., 2022). Preclinical studies indicate that dapansutrile not only attenuates inflammatory responses but also preserves bone structure by modulating extracellular matrix degradation (Yip et al., 2024). Notably, dapansutrile exhibits a synergistic effect when combined with lonafarnib, providing additional benefits in improving bone metabolic abnormalities in progeria animal models (Fu et al., 2025). This offers a theoretical basis for developing novel combination therapies targeting bone resorption in periodontitis.

In the field of neurodegenerative diseases, dapansutrile demonstrates potential in modulating neuro-inflammaging (Murda et al., 2022). Studies indicate that age-related chronic low-grade inflammation is a significant risk factor for neurodegenerative disorders such as Alzheimer’s disease (AD) (Abbatecola et al., 2024). The therapeutic potential of NLRP3 inflammasome inhibition by dapansutrile was demonstrated in a model of Alzheimer’s disease in mice. When six-month-old APP/PS1 mice were maintained for 3 months on an OLT1177-enriched diet, their age-dependent cognitive deficits were completely reversed. This was evidenced by a full rescue of learning and memory impairments in the Morris water maze test (P = 0.008 vs. untreated APP/PS1), which was accompanied by a significant restoration of synaptic plasticity (P = 0.007 vs. untreated APP/PS1). Furthermore, NLRP3 inhibition via OLT1177 reduced microglial activation (P = 0.07) and decreased cortical plaque burden (P = 0.03), highlighting its therapeutic potential for neuroinflammation (Lonnemann et al., 2020). However, the therapeutic effects of OLT1177 in humans remain unclear, and existing animal studies cannot definitively demonstrate that Dapansutrile has an absolute curative effect on Alzheimer’s disease. The recovery outcomes in advanced-stage subjects require further investigation. Thus, the efficacy of OLT1177 in late-stage Alzheimer’s disease may become a key objective for future research, which would provide a theoretical foundation for the clinical translation of this drug. Notably, OLT1177 reduced nuclear deformation in Hutchinson-Gilford progeria syndrome (HGPS) fibroblasts, attenuated senescence markers, and improved survival in *Lmna*G609G/G609G mice. Western blot and sequencing analyses showed that in vivo administration lowered NLRP3, active caspase-1, and IL-1β protein levels in cardiac and hepatic tissues of *Lmna*G609G/G609G models, suggesting neuroprotection via modulation of the central nervous system’s inflammatory microenvironment (Muela-Zarzuela et al., 2024). Neuroinflammation also plays a pivotal role in Parkinson’s disease (PD) pathology (Qian et al., 2010). Ellagic acid (EA), a natural polyphenol with neuroprotective effects in neurological disorders (Moura et al., 2015), suppresses NLRP3 inflammasome signaling and proinflammatory cytokine release in microglia. However, tyrosine hydroxylase (TH)-positive neuron counts and TH protein assays revealed no direct neuroprotection for dopaminergic neurons (He et al., 2020). The therapeutic potential of OLT1177 for neurodegenerative disorders is supported by evidence from MPTP-induced PD models, which shows that the inhibitor effectively crosses the blood-brain barrier, enabling it to reach concentrations that block NLRP3 assembly in the brain. Subsequent in vitro and in vivo animal experiments showed OLT1177 significantly reduced α-synuclein monomer/oligomer levels by enhancing microglial autophagy, thereby degrading α-synuclein, lowering proinflammatory cytokines, and protecting dopaminergic neurons and astrocytes (Amo-Aparicio et al., 2023).

In drug-induced experimental autoimmune encephalomyelitis model in mice, OLT1177-enriched chow reduced spinal cord levels of TNFα, CXCL-1, and IL-6 without affecting anti-inflammatory IL-10. Remarkably, OLT1177 also diminished spinal proinflammatory cytokines, immune cell infiltration, and prevented demyelination (Sanchez-Fernandez et al., 2019). While limited data exist on its BBB penetration, its systemic anti-inflammatory efficacy underscores the importance of developing targeted delivery systems for neuroinflammatory diseases.

Dapansutrile emerges as a promising candidate for modulating inflammaging, a core pathological process in age-related diseases characterized by low-grade chronic inflammation (Koppula et al., 2021). The condition manifests as a breakdown in inflammatory homeostasis, with sustained elevations in key mediators such as IL-1β and IL-18 (Giunta et al., 2022; Muller and Di Benedetto, 2024). When combined with the existing anti-aging drug lonafarnib, dapansutrile exhibits synergistic anti-inflammatory effects, more effectively reducing tissue inflammation levels and cellular senescence markers while blocking the production of senescence-associated secretory phenotype (SASP). This combination has been shown to significantly extend lifespan and ameliorate multiple aging-related defects in progeroid animal models (Muela-Zarzuela et al., 2024). This combined strategy provides novel insights for intervening in age-related conditions such as cardiovascular aging (Zeng et al., 2024) and metabolic disorders (Yuan et al., 2018), with its safety and efficacy preliminarily validated in Phase II clinical trials (Lonnemann et al., 2020).

Research has demonstrated that intra-articular injection of Dapansutrile in a rat osteoarthritis (OA) model significantly reduced Mankin and OARSI scores (joint degeneration evaluation metrics). A multi-level analysis revealed the broad impact of Dapansutrile on inflammatory and catabolic pathways. At the RNA level, it modulated key markers (Cox-2, iNOS, Mmp-3/9/13, IL-10), findings that were coherently confirmed at the protein level for COX-2, MMP-3/9/13, SOX-9, and COL2. Furthermore, Western blot analysis demonstrated that this regulatory effect involved the significant suppression of the MAPK signaling pathway, as evidenced by reduced phosphorylation of its key components ERK, JNK, and p38 (Cargnello and Roux, 2011). Specifically, Dapansutrile inhibited phosphorylated ERK and p38 expression, thereby attenuating MAPK pathway activation. This suppression led to reduced expression of matrix metalloproteinases (MMP3, 9, 13) and reversed the IL-1β-induced downregulation of type II collagen (COL2) and chondrogenic markers (SOX9, COL2), highlighting its anti-degenerative effects (Tang et al., 2022). Cartilage degeneration is often associated with TLR/NF-κB pathway activation (Yin et al., 2025). Dapansutrile’s inhibition of NLRP3 may indirectly regulate these pathways, suggesting its potential as a novel therapeutic strategy for joint and cartilage disorders.

In hepatitis-induced liver injury in mice, treatment with Dapansutrile was found to significantly reduce ALT/AST levels and ameliorate histopathological damage in liver tissue. Mechanistic studies revealed that the drug alleviates oxidative stress by increasing glutathione (GSH) and superoxide dismutase (SOD) levels while reducing malondialdehyde (MDA) levels. The observed reduction in critical inflammatory mediators, including NLRP3, TNF-α, IL-6, and IL-1β, is consistent with Dapansutrile acting through a mechanism that centrally involves the inhibition of key inflammatory pathways (Alenezi et al., 2025). In chemical-induced liver injury in mice, Dapansutrile suppresses the NLRP3 inflammasome, further reducing serum transaminases, IL-1β, and TNF-α expression levels. It also inhibits the cleavage of Caspase-1, IL-1β, and gasdermin D (GSDMD), improving DMF-induced infiltration of hepatic macrophages and neutrophils, thereby significantly attenuating liver injury (Zhang et al., 2024). In multiple clinical trials, Dapansutrile has demonstrated good safety and low hepatotoxicity (Wohlford et al., 2020). Notably, another NLRP3 inhibitor, MCC950, was found to pose potential hepatotoxicity risks in both animal studies and clinical trials, leading to the termination of its Phase I clinical program (Chen et al., 2023). In contrast, available reports have not indicated evidence of hepatotoxicity for Dapansutrile in animal models; instead, it has demonstrated protective effects against chemically-induced (e.g., Con A) and progeria-associated liver injury. Its favorable safety profile may stem from its specific inhibition of the NLRP3 inflammasome without interfering with other hepatic metabolic pathways (Muela-Zarzuela et al., 2024). Furthermore, Dapansutrile may serve as an adjunctive therapy in combination with lonafarnib for treating Hutchinson-Gilford progeria syndrome (HGPS), with mechanisms including reducing inflammation and delaying senescence-related phenotypes (Muela-Zarzuela et al., 2024), which indirectly supports its potential in treating chronic liver diseases.

Dapansutrile (OLT1177) demonstrates dual therapeutic effects in dextran sodium sulfate (DSS)-induced murine colitis models. Firstly, it significantly suppresses macrophage infiltration into damaged colonic mucosa and epithelial layers while reducing serum levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-18, TNF-α). Secondly, it upregulates ferritin heavy chain (FTH) expression, whose ferroxidase activity converts toxic Fe²⁺ to Fe³⁺ (Ferreira et al., 2001), thereby alleviating colonic iron overload and macrophage-mediated inflammation, a mechanism also linked to NLRP3 inhibition (Yu et al., 2025).

Notably, combination therapy with OLT1177 and BBG (a P2X7R blocker) synergistically reduces leukocyte infiltration, colon wall thickness, and improves histopathological scores. This regimen normalizes expression levels of NF-κB, IL-6, TNF-α, P2X7R, and NLRP3 in mice, while decreasing caspase-1, myeloperoxidase (MPO) activity, and caspase-3 expression. Intriguingly, OLT1177 monotherapy paradoxically elevates caspase-3 and MPO activity (Saber et al., 2021), suggesting complementary mechanisms between NLRP3 and P2X7R inhibition for colitis treatment.

These findings collectively underscore dapansutrile’s promise as a therapeutic target for inflammatory bowel diseases, highlighting its considerable potential for clinical translation.

Chemical renal toxicity is common, with limited therapeutic interventions available. In folic acid (FA)-induced acute kidney injury (AKI) in mice, DAPA injection improved renal tissue integrity, as evidenced by reduced glomerular tuft atrophy and necrosis accompanied by decreased interstitial inflammatory cell infiltration, ameliorated tubular dilation and necrosis, as well as diminished CD86-positive cell infiltration and lower fibrosis percentage. Functional biomarker analysis revealed significant reductions in caspase-1, IL-1β, and IL-18 (p < 0.05). The therapeutic relevance of DAPA was further evidenced by its reduction of Ki-67 (proliferation) and LC-3II (autophagy) (Elsayed et al., 2021). This supports a model where DAPA mitigates FA-induced nephrotoxicity not only by disrupting the core inflammasome/caspase-1/IL signaling axis but also by coordinately regulating associated pathways of renal regeneration and autophagy.

By targeting the NLRP3 inflammasome, dapansutrile inhibits pro-inflammatory cytokine release, modulates oxidative stress, and regulates extracellular matrix degradation. Consequently, it attenuates inflammatory responses in tissues and has demonstrated direct or indirect protective effects across multiple organ models, including the heart, joints, liver, and intestines (Detailed effects are shown in Table 2). Clinical studies in heart failure and osteoarthritis have confirmed its safety and preliminary efficacy (Klück et al., 2020; Wohlford et al., 2020). A comprehensive understanding of the mechanisms behind its organ protection awaits further study.

Current research indicates that polymer-based drug delivery systems (PDDS) play a crucial role in controlled drug release, though their complex structures and multiple influencing factors limit therapeutic outcomes with conventional methods (Han et al., 2016; Aghajanpour et al., 2025). Nanomicellar systems have been validated as effective carriers for combined anti-inflammatory and antioxidant therapies (Li et al., 2022c), offering valuable insights for optimizing dapansutrile delivery. AI-assisted nanocarriers also show unique advantages; integrated machine learning methods such as random forest and XGBoost genetic algorithms can effectively predict drug release behavior and guide the development of novel delivery systems (Khodadadi et al., 2025). Particularly, chemometrics-based predictive models have been successfully applied to optimize drug delivery platforms, significantly accelerating translation from bench to bedside (Perni and Prokopovich, 2020). Future studies should focus on developing targeted, activatable, and fluorescence imaging-guided nano-delivery systems for dapansutrile (Song et al., 2024), while leveraging molecular modeling and machine learning to optimize formulation design (Li et al., 2022d).

Artificial intelligence holds great potential in predicting combination therapies, especially for complex multi-drug regimens (Zhang et al., 2025). Integrated AI and physiologically based pharmacokinetic (PBPK) platforms can rapidly predict in vivo drug efficacy and related uncertainties based solely on molecular structures, and have successfully forecasted eight key drug properties (solubility, pKa, crystal density, intrinsic dissolution rate, apparent permeability, unbound fraction, plasma clearance, and tissue partition coefficients for 15 organs) (Wang et al., 2025). Computational approaches such as Gaussian process regression, combined with active learning and fine grid optimization, can predict the therapeutic effects of dual-drug-loaded nanoparticles with high efficiency using only 25% of experimental data (Jin et al., 2025). Existing studies show that machine learning models excel in predicting drug synergy and antagonism; predictive models integrating multi-source biological data provide a theoretical foundation for precision medicine (Lin et al., 2025). For optimizing dapansutrile-based combinations, perturbation theory–machine learning (PTML) models—already applied in screening drug–vitamin nano-systems for cancer combination therapy (Santana et al., 2019)—can be employed. Future research should emphasize the development of integrated algorithmic models capable of simultaneously predicting drug release profiles and synergistic efficacy (Bannigan et al., 2023), and establish specialized databases for predicting multi-drug combinations in inflammatory diseases (Chen et al., 2023).