Work

GenX induces offspring vascular endothelial ferroptosis by targeting GPX4 for ubiquitination-dependent degradation

Year: 2025

Type: article

Abstract: • Gestational GenX exposure causes fetal growth restriction and placental damage. • GenX induces offspring vascular maldevelopment and endothelial dysfunction. • GenX triggers endothelial ferroptosis via GSH/SOD depletion & MDA/Fe 2+ /ROS rise. • GenX binds GPX4, promoting its ubiquitination-mediated degradation. • GPX4 overexpression rescues GenX-induced ferroptosis & endothelial damage. GenX, a widely used replacement for PFOA, has become ubiquitously distributed in aquatic ecosystems, soil, and biota, yet its developmental toxicity in offspring is poorly characterized. This study delineates the intergenerational vascular consequences of gestational GenX exposure. Pregnant mice exposed to GenX exhibited adverse pregnancy outcomes, notably fetal growth restriction and placental structural impairment. Pathological evaluation demonstrated labyrinthine zone disorganization and diminished Occludin expression in placentas, indicating disrupted barrier function that likely facilitates maternal-fetal GenX transfer. Critically, exposed offspring displayed systemic vascular maldevelopment, marked by aberrant angiogenesis and endothelial dysfunction. Mechanistic investigations revealed that GenX provoked ferroptosis in vascular endothelial cells, evidenced by depleted GSH, suppressed SOD activity, elevated MDA and Fe 2+ levels, and mitochondrial ROS overproduction. Strikingly, GenX directly interacted with GPX4, a master ferroptosis suppressor, and accelerated its ubiquitination-mediated degradation. Functional rescue experiments confirmed that GPX4 overexpression abolished GenX-induced endothelial ferroptosis and restored vascular homeostasis. Our data establish GPX4 as the keystone target through which GenX disrupts offspring vascular development via ferroptosis. This work provides the crucial evidence connecting environmental GenX exposure to offspring’s endothelial dysregulation, uncovers a novel toxicological axis involving GPX4 destabilization, and underscores the importance of reassessing the developmental safety of GenX.

Source: Current Research in Toxicology

DOI: 10.1016/j.crtox.2025.100260

Authors: Jing Li, Yuhui Cui, Chengyi Zheng, Yiwei Zhang, Shuxian Li, Lingbing Li