2. Academic Validation
  3. Pyrvinium pamoate inhibits the survival of intracellular Mycobacterium tuberculosis through suppression of macrophage ferroptosis

Pyrvinium pamoate inhibits the survival of intracellular Mycobacterium tuberculosis through suppression of macrophage ferroptosis

  • Bioorg Chem. 2026 Jul 5:175:109753. doi: 10.1016/j.bioorg.2026.109753.
Qing Guan 1,  Yuanyuan Zhou 2,  Jian-Li Han 3,  Fangyi Guo 3,  Zhongkun Li 3,  Yidan Zhou 4,  Xiao-Lian Zhang 5
Affiliations

Affiliations

  • 1 Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, China; Department of Clinical Laboratory, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China.
  • 2 Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, China; Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 3 Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, China.
  • 4 Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China. Electronic address: [email protected].
  • 5 Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, China; State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, China. Electronic address: [email protected].
PMID: 41875752 DOI: 10.1016/j.bioorg.2026.109753
Abstract

Tuberculosis is a top killer among infectious diseases. Traditional tuberculosis treatment drugs have serious resistance issues and long treatment courses. Therefore, continuous improvement and new treatment strategies against TB are urgently required. Pyrvinium pamoate is a Food and Drug Administration (FDA) approved anthelminthic drug. Recently we have reported that pyrvinium pamoate can decrease mycobacterial burdens in Mycobacterium tuberculosis (M. tuberculosis)-infected macrophages and mice. However, the mechanism by which pyrvinium pamoate inhibits the survival of intracellular M. tuberculosis remains to be explored. In this study, we discovered that low dose (0.2 μg/mL, less than IC50, half-maximal inhibitory concentration) of pyrvinium pamoate could inhibit the survival of intracellular M. tuberculosis H37Rv/H37Ra growth through suppressing Ferroptosis of the infected macrophage. We found that pyrvinium pamoate could bind to Casein Kinase (CK)1α protein and suppress M. tuberculosis- or RSL3 (a well-known inducer of cell Ferroptosis)-induced lipid peroxidation Ferroptosis in macrophages through reducing ATF4-xCT-GSH-GPX4 expression and activation of YAP1-ACSL4 and TFRC-Fe3+ pathways. CK1α siRNA or its inhibitor D4476 can reverse above effects by pyrvinium pamoate on the Ferroptosis and intracellular M. tuberculosis survival. We unveil a previously unrecognized and multifaceted mechanism by which pyrvinium pamoate, via targeting CK1α, inhibits M. tuberculosis-induced Ferroptosis. We propose that pyrvinium pamoate holds great promise as a host-directed therapy (HDT) drug for mycobacterial-induced Ferroptosis.

Keywords

Drug repositioning; Drug repurposing; Ferroptosis; Mycobacterium tuberculosis; Pyrvinium pamoate.

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