Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

Abstract Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in specific section nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement necroptosis well characterized, genetic evidence supporting contribution ferroptosis lacking. Here, we demonstrate that loss suppressor protein 1 ( Fsp1 ) or targeted manipulation active center selenoprotein glutathione peroxidase 4 Gpx4 cys/- sensitize kidneys ferroptosis, resulting unique morphological pattern necrosis. Given unmet medical need clinically inhibit AKI, generated combined small molecule inhibitor (Nec-1f) simultaneously targets receptor interacting kinase (RIPK1) and cell lines, freshly isolated primary tubules mouse models cardiac transplantation AKI improved survival ischemia-reperfusion injury. Based on pharmacological evidence, conclude GPX4 dysfunction hypersensitizes mice ATN during AKI. Additionally, introduce Nec-1f, solid RIPK1 weak ferroptosis.