AIM2-NLRP3 Inflammasome Dual Inhibitor on hsCRP

The Effect of AIM2-NLRP3 Inflammasome Dual Inhibitor on hsCRP in Patients After Coronary Intervention Therapy

Residual inflammatory risk remains a major contributor to adverse cardiovascular outcomes despite guideline-directed therapy. Although colchicine reduces cardiovascular events, its anti-inflammatory effects may extend beyond NLRP3 inhibition to involve AIM2 inflammasome suppression. We hypothesized that dual NLRP3/AIM2 inhibition may provide an effective strategy for targeting residual inflammatory risk. Using molecular docking and a THP-1 cell-based dual-inflammasome model, we screened approved drugs and identified leflunomide, eplerenone, and artesunate as candidate agents with greater IL-1β inhibitory activity than colchicine at clinically relevant concentrations. These findings highlight dual inflammasome inhibition as a potential therapeutic strategy for coronary heart disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Inflammation; Coronary Heart Disease
• Intervention / Treatment: Drug: Colchicine; Drug: Eplerenone; Drug: Leflunomide; Drug: Artesunate

Detailed Description

Despite advances in contemporary preventive and therapeutic strategies, coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Residual inflammatory risk (RIR) persists in a substantial proportion of patients despite guideline-directed medical therapy and contributes to recurrent cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. Accumulating evidence has established inflammation as a key driver of atherosclerotic cardiovascular disease, highlighting the need for targeted anti-inflammatory therapies to address this unmet clinical need. Notably, two large-scale randomized controlled trials, COLCOT and LoDoCo2, demonstrated that low-dose colchicine reduces cardiovascular events in patients with coronary artery disease, providing compelling clinical evidence for the therapeutic potential of targeting inflammation. These findings subsequently led to the approval of colchicine by the US Food and Drug Administration (FDA) for the reduction of cardiovascular risk in adults with established atherosclerotic cardiovascular disease.

The anti-inflammatory effects of colchicine are thought to involve the disruption of microtubule dynamics and the suppression of NLRP3 inflammasome activation, thereby attenuating downstream interleukin (IL)-1β and IL-6 signaling and reducing high-sensitivity C-reactive protein (hsCRP) levels. Among the inflammasomes implicated in cardiovascular diseases, NLRP3 and AIM2 have emerged as important contributors to inflammatory signaling in atherosclerotic disease. However, whether effective attenuation of residual inflammatory risk requires simultaneous targeting of multiple inflammasome pathways remains unclear. In our previous studies, we evaluated three pharmacological inhibitors of the NLRP3 inflammasome in patients with CHD. Notably, only colchicine, a nonselective inhibitor of NLRP3 inflammasome activation, significantly reduced hsCRP levels, whereas the more selective NLRP3 inhibitors tranilast and oridonin did not produce a comparable effect. Given that colchicine can also suppress AIM2 inflammasome activation, these findings raise the possibility that its clinical anti-inflammatory efficacy may extend beyond NLRP3 inhibition. We therefore hypothesized that concomitant inhibition of the NLRP3 and AIM2 inflammasomes may represent a more effective therapeutic strategy for mitigating residual inflammatory risk in patients with CHD.

To explore this hypothesis and identify clinically available therapeutic alternatives, we performed an integrated drug-repurposing strategy combining molecular docking-based virtual screening with functional validation in a THP-1 cell-based model of dual NLRP3 and AIM2 inflammasome activation. By integrating inhibitory efficacy against both inflammasome pathways with clinically achievable plasma drug concentrations, we identified the candidate drugs with IL-1β inhibitory activity exceeding that of colchicine: leflunomide, eplerenone, and artesunate. These findings provide a rationale for further investigating dual inflammasome inhibition as a potential therapeutic approach to targeting residual inflammatory risk in CHD.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Volunteer to participate, understand and sign an informed consent form.
2. Age ≥ 18 years old, regardless of gender.
3. Patient diagnosed with coronary heart disease requiring percutaneous coronary intervention.
4. Complete all planned percutaneous coronary intervention during hospitalization.
5. Patient must be treated according to national guidelines for standard treatment of coronary heart disease.

Exclusion Criteria:

1. Known hypersensitivity or allergy to colchicine, eplerenone, leflunomide, or artesunate.
2. Use of colchicine, eplerenone, leflunomide, or artesunate within 30 days before screening.
3. Hepatic dysfunction, defined as alanine aminotransferase (ALT) levels greater than 3 times the upper limit of normal (ULN).
4. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m².
5. Hyperkalemia, defined as a serum potassium level greater than 5.0 mmol/L.
6. Thrombocytopenia, defined as a platelet count of less than 100 × 10⁹/L.
7. Leukopenia, defined as a white blood cell count of less than 3.0 × 10⁹/L.
8. Anemia, defined as a hemoglobin level of less than 90 g/L.
9. Requirement for potassium supplementation or potassium-sparing diuretics, including amiloride, spironolactone, triamterene, etc.
10. Current treatment with potent CYP3A4 inhibitors, including ketoconazole, itraconazole, clarithromycin, etc.
11. Uncontrolled infectious diseases.
12. Known immune diseases or immune-related diseases such as systemic lupus erythematosus, asthma, inflammatory bowel disease, gout, malignant tumor, etc.
13. Current or planned use of medications outside the study protocol that may affect immune or inflammatory responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, immunomodulatory agents, chemotherapeutic agents, etc.
14. Pregnant women, lactating women or women of childbearing age who do not use effective contraceptives.
15. Any other circumstances in which the investigator judges that the patient is not suitable to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Standard treatment for coronary heart disease
Experimental: Colchicine group; Colchicine+standard treatment for coronary heart disease	Drug: Colchicine; Colchicine 0.5mg PO Qd
Experimental: Eplerenone group; Eplerenone+standard treatment for coronary heart disease	Drug: Eplerenone; Eplerenone 50mg PO Qd
Experimental: Leflunomide group; Leflunomide+standard treatment for coronary heart disease	Drug: Leflunomide; Leflunomide 10mg PO Qd
Experimental: Artesunate group; Artesunate+standard treatment for coronary heart disease	Drug: Artesunate; Artesunate 50mg PO Bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in hsCRP	The change in hsCRP compared to baseline	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major adverse cardiac and cerebrovascular event (MACCE)	Composite endpoint of all cause death, non fatal myocardial infarction, non fatal stroke, and revascularization due to ischemia	4 weeks
Plasma OLINK proteomics detection	The change in plasma OLINK proteomics	4 weeks
Peripheral blood mononuclear cell mass spectrometry proteomics detection	The change in peripheral blood mononuclear cell mass spectrometry proteomics	4 weeks
Blood drug concentration	Blood drug concentration in different interventions	4 weeks

Collaborators and Investigators

• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Publications and helpful links

General Publications

• Yu M, Sun MY, Yang F, Yuan YF, Zhang YM, Ruan CC, Ji Y, Libby P, Cheng X. Taming inflammation in coronary artery disease: lessons learned, translational breakthroughs, and future directions. Sci Bull (Beijing). 2026 Sep 30:S2095-9273(26)01206-5. doi: 10.1016/j.scib.2026.09.081. Online ahead of print.
• Yu M, Zhu ZF, Yang F, Yuan YF, Liao SD, Liu ML, Cheng X. Different Anti-inflammatory Drugs on High-Sensitivity C-Reactive Protein in Patients After Percutaneous Coronary Intervention: A Pilot Randomized Clinical Trial. J Cardiovasc Pharmacol. 2024 Mar 1;83(3):234-242. doi: 10.1097/FJC.0000000000001509.

Study record dates

Study Major Dates

• Study Start (Estimated): November 10, 2026
• Primary Completion (Estimated): February 10, 2027
• Study Completion (Estimated): November 10, 2027

Study Registration Dates

• First Submitted: November 6, 2026
• First Submitted That Met QC Criteria: November 6, 2026
• First Posted (Actual): November 12, 2026

Study Record Updates

• Last Update Posted (Actual): November 12, 2026
• Last Update Submitted That Met QC Criteria: November 6, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Myocardial Ischemia; Pathological Conditions, Signs and Symptoms; Inflammation; Coronary Disease; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Terpenes; Alkaloids; Polycyclic Compounds; Inorganic Chemicals; Pregnanes; Steroids; Fused-Ring Compounds; Lactones; Pregnenes; Reactive Oxygen Species; Free Radicals; Artemisinins; Sesquiterpenes; Isoxazoles; Leflunomide; Artesunate; Eplerenone; Colchicine
• Other Study ID Numbers: ANDI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No