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

Summary

This study identifies a Piezo1-driven mechanotransduction pathway in endothelium where BHLHE40 transcriptionally upregulates SLC7A11 to prevent ferroptosis and dampen inflammation. Endothelial BHLHE40 overexpression mitigated LPS-induced lung vascular leakage and inflammatory responses in vivo, positioning this axis as a therapeutic target in sepsis-related vascular injury.

Key Findings

• Shear stress activates Piezo1 leading to Ca2+/calcineurin-dependent NFAT2 nuclear translocation and formation of an NFAT2–HDAC1 complex that induces BHLHE40.
• BHLHE40 directly upregulates SLC7A11, enhancing cystine import, reducing ROS and lipid peroxidation, and conferring ferroptosis resistance in endothelial cells.
• Endothelial BHLHE40 overexpression attenuates LPS-induced lung vascular leakage, neutrophil infiltration, and pro-inflammatory cytokine release in vivo.

Clinical Implications

While preclinical, this axis suggests druggable nodes (Piezo1 signaling, BHLHE40, SLC7A11) to stabilize the endothelium in sepsis. It also motivates biomarker strategies around ferroptosis and endothelial injury.

Limitations

• Preclinical models may not capture heterogeneity of human sepsis and comorbid states.
• Therapeutic window, dosing, and safety of targeting this axis remain untested in humans.

Future Directions

Evaluate pharmacologic modulation (Piezo1 agonists/antagonists, BHLHE40 or SLC7A11 enhancers) in clinically relevant sepsis models; develop endothelial ferroptosis biomarkers; explore interactions with hemodynamics and vasopressor therapy.