2. Academic Validation
  3. Repurposing zafirlukast confers renal protection in ischemia-reperfusion injury via suppressing macrophage METosis

Repurposing zafirlukast confers renal protection in ischemia-reperfusion injury via suppressing macrophage METosis

  • Int Immunopharmacol. 2025 Sep 8:165:115459. doi: 10.1016/j.intimp.2025.115459.
Xiaochun Ye 1,  Yanqun Dong 2,  Jiaye Han 3,  Yumei Huang 1,  Meiyun Wen 4,  Ruofang Zheng 5,  Ping Wang 4,  Ran Chen 4,  Longwei Zhao 6
Affiliations

Affiliations

  • 1 Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
  • 2 Innovation Unit for Research and Clinical Translation of Cell Growth Factors and Disease, Institute of Materia Medical, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
  • 5 Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 6 Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China; Department of Pharmacology, School of Basic Medical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China; State Key Laboratory for Macromolecule Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: longwei-zhao@wmu.edu.cn.
PMID: 40925201 DOI: 10.1016/j.intimp.2025.115459
Abstract

Tacrolimus is widely used to prevent post-transplant acute kidney injury (AKI) but causes severe toxicities (e.g., nephrotoxicity, hyperglycemia). We repurposed zafirlukast (ZFK), an FDA-approved asthma drug, to address this limitation. In a murine kidney ischemia-reperfusion injury (KIRI) model, ZFK significantly attenuated renal dysfunction, reducing serum creatinine and blood urea nitrogen (BUN) to levels comparable to tacrolimus, without inducing metabolic adverse effects. RNA Sequencing revealed that ZFK recapitulated tacrolimus' anti-inflammatory gene signatures while uniquely suppressing macrophage extracellular trap formation (METosis). Mechanistically, ZFK inhibited METosis by downregulating PAD4 and CitH3 expression, confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomics (Tabula Muris and Human database) identified macrophages as the primary target via CysLT1R antagonism. This study provides the first evidence that ZFK protects against KIRI by targeting METosis, a key driver of sterile inflammation. Given its established safety profile, ZFK could bypass Phase I trials, accelerating clinical translation as a safer alternative to Calcineurin inhibitors. Our findings also highlight the broader potential of ZFK in METs-related diseases (e.g., sepsis, atherosclerosis) and underscore drug repurposing as a strategic approach for rapid therapeutic development.

Keywords

Drug repurposing, Zafirlukast (ZFK); Kidney ischemia/reperfusion injury (KIRI); METosis; Macrophage extracellular traps (METs); Translational medicine.

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