Mechanical stretch accelerates endothelial cell injury by inducing endoplasmic reticulum stress-mediated,...

Portal hypertension is characterized by elevated pressure within the portal venous system, commonly resulting from cirrhosis. As portal hypertension progresses, the portal vein dilates and subjected its endothelial cells (ECs) to mechanical stretch. In this study, we employed a flexible strain system to simulate the mechanical stretch experienced by ECs under portal hypertensive conditions. Our results revealed that mechanical stretch induced iron overload in ECs, triggering ferroptosis and endothelial dysfunction. Simultaneously, mechanical stretch activated autophagy in ECs, and inhibition of autophagy reduced ferritin degradation and alleviated iron overload. Moreover, endoplasmic reticulum (ER) stress transcriptionally upregulated NCOA4 expression, promoting NCOA4-mediated ferritinophagy. These findings demonstrate that mechanical stretch triggered ER stress in ECs, initiated NCOA4-mediated ferritinophagy, which led to iron overload and contributed to ferroptosis and endothelial dysfunction. Targeting ferritinophagy may help mitigate EC injury and dysfunction caused by mechanical stretch in the context of portal hypertension, offering a promising therapeutic approach for the prevention and treatment of portal vein thrombosis (PVT).