STING-FSP1 signaling drives endothelial ferroptosis and vascular leakage in sepsis

Sepsis-induced vascular endothelial injury, characterized by Ferroptosis and barrier dysfunction, remains a major cause of mortality. This study investigates the role of the stimulator of interferon genes (STING)/Ferroptosis suppressor protein 1 (FSP1) pathway in mediating endothelial Ferroptosis during sepsis and explores therapeutic interventions. A murine sepsis model was established using cecal ligation and puncture (CLP), along with LPS-stimulated human umbilical vein endothelial cells (HUVECs). STING activation was modulated using inhibitor H-151 and siRNA silencing. Ferroptosis was assessed through lipid peroxidation (MDA, BODIPY C11), Fe²⁺ accumulation (FerroOrange), and FSP1/GPX4 expression. Vascular permeability was quantified via Evans Blue extravasation and FITC-Dextran assays. STING activation in septic endothelial cells suppressed FSP1 expression, amplifying lipid peroxidation and Ferroptosis. CLP mice exhibited elevated vascular leakage, which H-151 reversed. STING inhibition restored FSP1 levels, reduced Fe²⁺ overload, and preserved VE-cadherin integrity. FSP1 inhibition abolished these protective effects, confirming its necessity in STING-mediated Ferroptosis. The STING/FSP1 axis exacerbates septic endothelial injury by driving Ferroptosis. Targeting this pathway reduces oxidative stress and vascular dysfunction, highlighting its therapeutic potential for sepsis.

FSP1; Ferroptosis; STING; Vascular endothelial damage; sepsis.