2. Academic Validation
  3. Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction

Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction

  • Biochem Pharmacol. 2025 Feb 12:234:116801. doi: 10.1016/j.bcp.2025.116801.
Xiuhui Chen 1,  Yunjing Wang 2,  Junjun Huang 2,  Huaqian Dou 2,  Zhe Zhang 3,  Yutong Zheng 1,  Rui Long 4,  Xiaofeng Zhang 5,  Fengdan Xu 6,  Weijun Ye 7,  Qing Xiao 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, the Eighth People' s Hospital of Dongguan, Dongguan Children' s Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China; Key Laboratory of Precision Pharmacy and Pharmaceutical Basic Research, Dongguan Institute of Pediatrics, the Eighth People's Hospital of Dongguan, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 Department of Cardiovascular Medicine & the Eighth People's Hospital of Dongguan, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China.
  • 4 Department of Neonatology, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China.
  • 5 Department of Pharmacy, the Eighth People' s Hospital of Dongguan, Dongguan Children' s Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China.
  • 6 Department of Neonatology, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China. Electronic address: xufengdan@gdmu.edu.cn.
  • 7 Department of Pharmacy, the Eighth People' s Hospital of Dongguan, Dongguan Children' s Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China; Key Laboratory of Precision Pharmacy and Pharmaceutical Basic Research, Dongguan Institute of Pediatrics, the Eighth People's Hospital of Dongguan, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China. Electronic address: yeweijun@ba-hospital.com.
  • 8 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: 2012990009@gzhmu.edu.cn.
PMID: 39952330 DOI: 10.1016/j.bcp.2025.116801
Abstract

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.

Keywords

Inflammation; Molecular target; Myocardial infarction; NACHT domain; NLRP3 inflammasome; Tamibarotene.

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