Endothelial Mechanosensitive Transcription Factor BHLHE40 Induced by Piezo1 Orchestrates Endothelial Inflammation and Ferroptosis via SLC7A11
Endothelial dysfunction-driven vascular inflammation underlies sepsis and atherosclerosis, yet the transcriptional pathways linking mechanical sensing to anti-inflammatory protection remain poorly defined. Piezo1 serves as a central mediator for endothelial mechanosensation and inflammatory homeostasis, while the exact composition of its downstream3 signaling cascade remains incompletely resolved. Here, we identify BHLHE40 as an en dothelial mechanosensitive transcription factor induced by Piezo1 that coordinates ferroptosis resistance and inflammation suppression. Mechanistically, shear stress activates Piezo1, triggering Ca 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 were demonstrate this phenomenon. Crucially, endothelial specific BHLHE40 overexpression attenuates LPS-induced lung vascular leakage, neutrophil infiltration, and pro-inflammatory cytokine release.