INTRODUCTION
Atherosclerosis remains the primary pathological foundation of cardiovascular diseases (CVD), the leading cause of global morbidity and mortality (1). It is a progressive chronic disease starting in childhood, characterized by lipid-rich plaque accumulation on arterial walls, leading to vascular dysfunction and ischemic events (1, 2). Low-density lipoprotein cholesterol (LDL-C) is a causal factor in atherogenesis (2). However, even after successful LDL-C control, significant residual cardiovascular risk persists, indicating involvement of other pathogenic processes, including inflammation (3).
Conventional therapies targeting plasma lipids, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, reduce LDL-C and plaque burden but do not eliminate cardiovascular risk (3). The interplay between lipid accumulation and vascular inflammation is critical in plaque formation and destabilization (4). Oxidized low-density lipoprotein (ox-LDL) and cholesterol crystals act as powerful triggers of inflammatory signaling, enhancing vascular damage and plaque vulnerability (5).
The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is central to the inflammatory cascade in atherosclerosis (3, 5). It is activated by cholesterol crystals and ox-LDL, leading to interleukin-1β (IL-1β) and interleukin-18 (IL-18) maturation and secretion, thereby amplifying local and systemic inflammation (5, 6). The canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial confirmed that IL-1β inhibition reduces recurrent cardiovascular events, providing proof-of-concept that targeting NLRP3 inflammasome signaling offers benefits beyond lipid lowering (7, 8).
Nevertheless, translating NLRP3 inhibitors into clinical use faces challenges such as off-target effects and poor stability. Small-molecule inhibitors like MCC950 and tranilast show efficacy in preclinical models (9, 10), and natural compounds such as baicalin also inhibit NLRP3-mediated inflammation (11). Machine learning and molecular dynamics simulations are accelerating inhibitor discovery (12).
Thus, this review synthesizes current knowledge on NLRP3 inflammasome in atherosclerosis pathophysiology and critically evaluates the development status of NLRP3 inhibitors, focusing on preclinical and clinical drug design approaches (13–15). Fig. 1 provides a schematic view of NLRP3 inflammasome activation in atherosclerosis.
Fig. 1. Schematic representation of NLRP3 inflammasome activation in atherosclerosis. NLRP3 inflammasome activation follows a two-signal mechanism in atherosclerosis: signal 1 (priming) is mediated by TLR4/LDLR activation and NF-κB nuclear translocation, leading to upregulation of NLRP3 and pro-IL-1β; signal 2 (activation) is triggered by atherogenic stimuli such as cholesterol crystals, oxidized LDL (ox-LDL), reactive oxygen species (ROS), potassium efflux, lysosomal rupture, and mitochondrial damage, leading to NLRP3 oligomerization, ASC speck formation, and caspase-1 activation; activated caspase-1 processes pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, and induces pyroptosis via gasdermin D (GSDMD). These events ultimately promote vascular inflammation, plaque instability and rupture.
NLRP3 INFLAMMASOME: STRUCTURE, ACTIVATION AND PATHOPHYSIOLOGICAL ROLES IN ATHEROSCLEROSIS
NLRP3 inflammasome structure and assembly mechanism
The NLRP3 inflammasome is a multiprotein complex of the innate immune system, consisting of the NLRP3 receptor, the adaptor protein [apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)](ASC), and caspase-1 (16). Structurally, NLRP3 contains a nucleotide-binding oligomerization domain (NACHT), leucine-rich repeats (LRRs), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes and recruits ASC via PYD-PYD interactions. ASC aggregates then recruit and activate pro-caspase-1, which processes pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18 (16, 17). In addition, caspase-1 cleaves gasdermin D to initiate pyroptosis (17).
NLRP3 activation follows a two-signal mechanism: signal 1 (priming) upregulates NLRP3 and pro-IL-1β via NF-κB; signal 2 (activation) triggers inflammasome assembly upon danger signals such as reactive oxygen species (ROS), potassium efflux, lysosomal rupture, and mitochondrial dysfunction (18). Cryo-electron microscopy has revealed an inactive double-ring NLRP3 structure that prevents spontaneous activation (19). NEK7 is required for NLRP3 oligomerization (20), and receptor for activated C kinase 1 (RACK1) promotes active conformation (21). Ubiquitination and deubiquitination (e.g., by ABRO1) regulate NLRP3 stability (22). Atranorin directly targets ASC to block inflammasome assembly (23). These findings identify multiple steps as promising therapeutic targets (16–24).
Function of NLRP3 inflammasome in atherosclerotic plaque formation and instability
NLRP3 inflammasome activation in plaque macrophages releases IL-1β and IL-18, promoting inflammatory cascades, immune cell recruitment, and foam cell formation (25, 26). It also triggers pyroptosis of endothelial cells and macrophages, contributing to necrotic core expansion and plaque vulnerability (27). Moreover, NLRP3 regulates matrix metalloproteinases (MMPs), degrading the fibrous cap and predisposing to plaque rupture (28).
Clinical and experimental evidence shows elevated NLRP3 activity in human plaques, correlating with disease severity (25). Tranilast, which enhances NLRP3 ubiquitination, attenuates vascular inflammation and atherosclerosis in murine models (10). Genetic or pharmacological NLRP3 ablation reduces endothelial inflammation, adhesion molecules (e.g., ICAM-1, VCAM-1), and macrophage infiltration (26, 27). Non-coding RNAs, such as microRNAs and lncRNAs, have emerged as novel regulators of NLRP3 expression (29). Thus, the NLRP3 inflammasome is a key therapeutic target for preventing acute cardiovascular events (8, 10, 25–32).
Related signaling pathways and regulatory mechanisms
Table I systematically summarizes major signaling pathways and regulatory mechanisms involved in NLRP3 inflammasome activation, emphasizing their relevance to atherosclerosis. The table classifies priming pathways (e.g., NF-κB), activation triggers (e.g., potassium efflux, mitochondrial ROS), post-translational modifications, autophagy, epigenetic regulation, and non-coding RNA networks. It highlights key molecular constituents, their specific functions, and pathophysiological consequences in plaque formation and instability (33–38).
Table I. Key signaling pathways and regulators of NLRP3 inflammasome activation in atherosclerosis
a For each pathway or regulatory process, the key molecular components, specific role in NLRP3 activation, pathophysiological implications in atherosclerotic plaque formation and progression, therapeutic targeting potential, and supporting references (far-right column) are listed.
Table II. Representative NLRP3 inflammasome inhibitors and their preclinical/clinical development statusa
a For each inhibitor, the compound class, mechanism of action, preclinical efficacy in atherosclerosis models, clinical trial status, key translational challenges, and supporting references (far-right column) are summarized. Citation numbers correspond to the main reference list.
NF-κB activation via TLRs upregulates NLRP3 and pro-IL-1β (33, 34). Post-translational modifications, including ubiquitination, phosphorylation and deubiquitination, regulate NLRP3 stability and assembly. For example, ABRO1 promotes deubiquitination and activation, while tranilast enhances ubiquitination to inhibit inflammasome formation (22, 35). Mitochondrial dysfunction releases mtROS and mtDNA as danger signals (36). Signal transducer and activator of transcription 3 (STAT3) facilitates NLRP3 translocation to mitochondria (37). Potassium efflux via P2X7 and gasdermin D pores is a well-known activation trigger (38). Endoplasmic reticulum (ER) stress and lysosomal damage also promote NLRP3 activation (39). Autophagy, especially chaperone-mediated autophagy, degrades NLRP3 components (40). Histone deacetylase 3 (HDAC3) epigenetically regulates NLRP3 transcription (41), and microRNAs fine-tune its expression (29). These interconnected regulatory processes offer numerous potential therapeutic targets (10, 29, 33–41).
NLRP3 INFLAMMASOME INHIBITORS: DESIGN STRATEGIES AND PHARMACOLOGICAL PROPERTIES
As shown in Fig. 2, NLRP3 inflammasome inhibitors are divided into three major groups based on their mode of action: (i) small-molecule inhibitors (e.g., MCC950, IFM-2427) which directly inhibit NLRP3 ATPase activity or protein-protein interactions; (ii) biologic inhibitors (e.g., canakinumab) which block downstream cytokines; (iii) direct assembly disruptors (e.g., atranorin) which inhibit ASC oligomerization or caspase-1 activation (42, 43).
Fig. 2. Classification of NLRP3 inflammasome inhibitors by mechanism of action: class 1 including small-molecule inhibitors that directly inhibit NLRP3 ATPase activity, or block protein-protein interactions (e.g., MCC950, IFM-2427, INF39, CY-09); class 2 comprising biological inhibitors, including monoclonal antibodies targeting IL-1-09 that directly inhibit NLRP3 ATPase activity, or block protein-protein interactions (e.g., canakinumab); class 3 including direct assembly disruptors which inhibit ASC oligomerization and promote NLRP3 ubiquitination (e.g., atranorin, tranilast).
Chemical structures and mechanisms of small-molecule inhibitors
Small-molecule NLRP3 inhibitors show great therapeutic potential. MCC950, a diarylsulfonylurea-containing molecule, selectively inhibits NACHT domain ATPase activity, preventing NLRP3 oligomerization and inflammasome assembly (42, 44). IFM-2427, a sulfonylurea derivative with good oral bioavailability, targets NLRP3 ATPase and shows efficacy in preclinical cardiovascular models (45). Chalcone-based scaffolds contain α,β-unsaturated carbonyl groups as Michael acceptors, allowing covalent or non-covalent interactions with cysteine residues (46). INF39 irreversibly blocks NEK7-NLRP3 and NLRP3-ASC interactions (19). Molecular docking studies have guided structure-activity relationship (SAR) optimization to improve pharmacokinetics and reduce off-target effects (47). Future optimization will focus on selectivity, stability and oral bioavailability (19, 42–47).
Biologics and novel drug delivery systems
Biologic agents, including monoclonal antibodies and nucleic acid therapeutics [small interfering RNA (siRNA), antisense oligonucleotides], are being explored for NLRP3 inhibition (48, 49). However, they face challenges in cellular uptake and stability.
Fig. 3 details advanced drug delivery systems to improve targeted delivery of NLRP3 inhibitors to atherosclerotic plaques. These include liposomes, polymeric nanoparticles, and biomimetic vesicles, which enhance solubility, prolong circulation, and enable controlled release (50). Targeting strategies such as ligand-receptor interactions (e.g., VCAM-1 or scavenger receptors) and stimuli-responsive release (pH- or ROS-sensitive systems) exploit the plaque microenvironment for site-specific delivery (51). Peptide-based carriers and DNA nanodevices offer biocompatibility and programmability (52). Despite advances, further optimization of stability, scalability and penetration depth is needed before clinical application (48, 49).
Fig. 3. Schematic overview of advanced drug delivery systems for NLRP3 inflammasome inhibitors in atherosclerosis. Nanocarriers (liposomes, polymeric nanoparticles, biomimetic vesicles, peptide-based carriers) enhance drug solubility and prolong circulation time. Targeting strategies include passive accumulation via the enhanced permeability and retention (EPR) effect, active targeting through ligand-receptor interactions (e.g., VCAM-1 or scavenger receptors on macrophages), stimuli-responsive release triggered by acidic or oxidative plaque microenvironment, and mechano-responsive activation by shear stress or ultrasound. These approaches achieve site-specific drug accumulation, controlled release, and reduced systemic toxicity.
Pharmacological data and preclinical research outcomes
Preclinical studies in animal models of atherosclerosis show that NLRP3 inhibitors reduce plaque inflammation and volume and enhance stability. MCC950 treatment in murine models suppresses IL-1β release, reduces macrophage recruitment, and limits necrotic core growth (42, 47). Dose-dependent efficacy is observed, with higher doses showing greater inflammasome suppression. Safety profiles indicate that selective NLRP3 inhibition does not cause broad immunosuppression, reducing infection risk compared to upstream cytokine blockade (53). CY-09 has shown renoprotective effects in diabetic nephropathy models (54). However, limitations remain, including lack of pharmacokinetic data, off-target interactions, and difficulty achieving therapeutic tissue concentrations in humans (55). Biomarkers to monitor inflammasome activity are lacking, hindering clinical translation. These issues must be addressed through thorough pharmacological characterization and development of sensitive diagnostic tools (42, 47, 53–55).
CLINICAL PROGRESS AND CHALLENGES OF NLRP3 INFLAMMASOME INHIBITORS
Representative clinical candidate drugs and their clinical trial data
Table II summarizes representative NLRP3 inflammasome inhibitors, classifying them by compound type, mechanism of action, preclinical efficacy in atherosclerosis models, clinical trial status, and key translational challenges. The table lists small-molecule inhibitors (e.g., MCC950, IFM-2427, tranilast) and biologic agents (e.g., canakinumab), demonstrating the variety of therapeutic approaches targeting the NLRP3 pathway. Several compounds have advanced to clinical trials, while others remain in preclinical development, each facing distinct hurdles such as bioavailability, tissue specificity, and long-term safety (56, 57).
IFM-2427 is a promising candidate in clinical trials for inflammatory diseases, including atherosclerosis (53). Trial designs are generally randomized, placebo-controlled, evaluating biomarkers (e.g., IL-1β levels) and clinical endpoints (cardiovascular event reduction). Safety assessments focus on liver toxicity and gastrointestinal adverse effects (55). Early-phase data for IFM-2427, ZYIL1, DFV890, and OLT1177 show good pharmacokinetics and pharmacodynamics, with evidence of inflammasome inhibition (58). However, long-term cardiovascular outcome data and off-target effects remain insufficient. The anti-inflammatory benefits must be balanced against risks such as immunosuppression and infection vulnerability (53, 55, 58).
Challenges of tissue targeting and drug delivery
Plaque heterogeneity, including lipid cores, fibrous caps, inflammatory infiltrates and calcifications, affects drug distribution and bioavailability (59). Dense extracellular matrix and altered vascular permeability hinder small-molecule penetration. To overcome these barriers, chemical modification to increase lipophilicity and receptor-mediated targeting have been explored. Nanoparticle-based delivery systems, including liposomes, polymeric nanoparticles, and biomimetic nanovesicles, have shown promise (50, 51). These systems exploit ligand-receptor interactions (e.g., targeting integrins or scavenger receptors) and stimuli-responsive release triggered by acidic or oxidative plaque microenvironment (52). Mechano-responsive nanoplatforms activated by shear stress or ultrasound are also being developed. Nevertheless, achieving precise targeting while minimizing systemic exposure and off-target effects remains challenging. Optimization of nanoparticle size, surface chemistry and payload stability are critical.
Safety issues and balancing immune regulation
Long-term NLRP3 inhibition raises concerns about immunosuppression and increased infection risk, given the inflammasome's role in innate immunity and host defense. Chronic blockade may impair pathogen response, leading to opportunistic infections. Some inhibitors show manageable safety profiles in trials, but vigilance against immunosuppressive adverse events is essential (53). Strategies to minimize risks include specific targeting of activation pathways, intermittent dosing, and development of inhibitors that preserve basal immune functions while blocking pathological activation. Patient selection and monitoring based on biomarkers may help identify suitable candidates. Localized delivery systems to limit systemic exposure may also improve safety. Natural small-molecule inhibitors offer favorable biocompatibility profiles (53). Ultimately, balancing anti-inflammatory efficacy with immune homeostasis requires a deep understanding of inflammasome biology and careful clinical assessment (53). A comprehensive overview of future opportunities and remaining challenges in this field is presented in Fig. 4.
Fig. 4. Future directions and challenges in NLRP3 inflammasome-targeted therapy for atherosclerosis. Developmental scheme includes precision medicine using biomarkers, combination regimens with statins or PCSK9 inhibitors, novel drug design for improved selectivity and oral bioavailability, and next-generation smart nano-platforms for targeted delivery. Persistent challenges stay still in achieving tissue-specific targeting, maintaining immune homeostasis, overcoming clinical translation barriers, and addressing pharmacological limitations such as poor bioavailability and stability – success depending on integrated, multidisciplinary approaches bridging basic research, translational studies, and clinical development, with an emphasis on patient-centric outcomes and personalized treatment strategies.
CONCLUSIONS
The NLRP3 inflammasome has emerged as a key modulator of inflammatory pathways in atherosclerosis, providing insights into residual cardiovascular risk. Recent progress in small-molecule inhibitors and biologics shows promising therapeutic potential. However, challenges such as poor tissue-specific targeting, off-target effects, and the delicate balance of immune homeostasis remain major hurdles. Future research should enhance mechanistic understanding of NLRP3 activation in the vascular microenvironment, guiding the rational design of next-generation inhibitors with improved specificity and pharmacokinetics. Novel drug delivery systems enabling targeted release to diseased vascular tissues are also promising. Integrating these approaches with precision medicine, using biomarkers and patient stratification, will be essential to optimize clinical effectiveness and safety.
Overall, inhibition of the NLRP3 inflammasome holds the potential to revolutionize atherosclerosis treatment by addressing residual inflammatory risk, ultimately reducing cardiovascular morbidity and mortality.
Acronyms, abbreviations, symbols. – ASC – apoptosis-associated speck-like protein containing a CARD, CANTOS – canakinumab anti-inflammatory thrombosis outcomes study, CARD – caspase recruitment domain, CVD – cardiovascular diseases, ER – endoplasmic reticulum, HDAC3 – histone deacetylase 3, IL-1β – interleukin-1β, IL-18 – interleukin-18, LDL-C – low-density lipoprotein cholesterol, LRR – leucine-rich repeat, MMP – matrix metalloproteinase, NACHT – nucleotide-binding oligomerization domain, NLRP3 – nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3, ox-LDL – oxidized low-density lipoprotein, PCSK9 – proprotein convertase subtilisin/kexin type 9, PYD – pyrin domain, RACK1 – receptor for activated C kinase 1, ROS – reactive oxygen species, SAR – structure-activity relationship, siRNA – small interfering RNA, SP1 – specificity protein 1, STAT3 – signal transducer and activator of transcription 3.
Data availability. – The data used to support the findings of this study are included within the article.
Declaration. – During the preparation of this manuscript, the author(s) used KIMI (https://kimi.moonshot.cn/) for language editing. After its use, the author(s) thoroughly reviewed, verified, and revised all AI-assisted content to ensure accuracy and originality. The authors take full responsibility for the integrity and final content of the published article.
Conflict of interest. – The author declares no conflicts of interest.
Funding. – This study is supported by Zhejiang Traditional Chinese Medicine Science and Technology Plan Project (2024ZL330).
Author’s contribution. – Conceptualization X.D.; data collection and data analysis L.B.; writing, original draft preparation, X.D; writing, review and editing X.D. and L.B. Both authors have read and agreed to the published version of the manuscript.
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