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

## TL;DR

This study reveals how mechanical forces protect blood vessel cells from inflammation and cell death through a chain of molecular events involving Piezo1 and BHLHE40.

## Contribution

The paper identifies a novel mechanotransduction pathway linking Piezo1 to BHLHE40 and SLC7A11 to suppress ferroptosis and inflammation in endothelial cells.

## Key findings

- BHLHE40 is a mechanosensitive transcription factor induced by Piezo1 to upregulate SLC7A11 and inhibit ferroptosis.
- Endothelial-specific BHLHE40 overexpression reduces inflammation and vascular leakage in mice.
- The Piezo1/Ca²⁺/calcineurin/NFAT2-HDAC1/BHLHE40/SLC7A11 axis maintains endothelial homeostasis.

## 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.