2. Academic Validation
  3. Endothelial mechanosensitive transcription factor BHLHE40 induced by Piezo1 suppresses endothelial ferroptosis and inflammation via SLC7A11

Endothelial mechanosensitive transcription factor BHLHE40 induced by Piezo1 suppresses endothelial ferroptosis and inflammation via SLC7A11

  • Cell Death Discov. 2025 Dec 10. doi: 10.1038/s41420-025-02909-8.
Sihan Miao # 1,  Xiaoyi Dai # 1,  Xiya Li # 2,  Zhenghua Chen 1,  Yuqian Wang 3,  Tingting Ye 2,  Yuhan Ying 1,  Yixuan Yu 4,  Ailing Wu 5,  Hai Song 2,  Peng Teng 6,  Liang Ma 7,  Qi Zheng 8
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Life Sciences Institute, The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 School of Medicine, Zhejiang University, Hangzhou, China.
  • 4 Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 5 Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.
  • 6 Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 7 Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 8 Department of Cardiovascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41372156 DOI: 10.1038/s41420-025-02909-8
Abstract

Endothelial dysfunction-driven vascular inflammation underlies sepsis and atherosclerosis. Piezo1 serves as a central mediator for endothelial mechanotransduction and inflammatory homeostasis. Nevertheless, the transcriptional pathways linking mechanical sensing to anti-inflammatory protection and the exact composition of its downstream signaling cascade remain incompletely resolved. Here, we identify BHLHE40 as an endothelial mechanosensitive transcription factor induced by Piezo1 that coordinates Ferroptosis resistance and inflammation suppression. Mechanistically, shear stress activates Piezo1, triggering Ca²⁺ influx and calcineurin-dependent NFAT2 nuclear translocation. NFAT2 recruits HDAC1 to form a transcriptional complex that directly drives BHLHE40 expression. BHLHE40 then binds the SLC7A11 promoter, upregulating this cystine transporter to inhibit Ferroptosis. Rescued mitochondrial integrity, reduced ROS, and reversed lipid peroxidation demonstrated this phenomenon. Crucially, mice with endothelial-specific BHLHE40 overexpression attenuate LPS-induced lung vascular leakage, neutrophil infiltration, and pro-inflammatory cytokine release. Our work establishes the Piezo1/Ca²⁺/Calcineurin/NFAT2-HDAC1/BHLHE40/SLC7A11 axis as a master mechanotransduction pathway that transcriptionally maintains endothelial homeostasis.

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