USP7 upregulated by TGF-β1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury

Our work aimed to investigate the interactive roles of transforming growth factor β1 (TGF-β1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in Ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that Ferroptosis was aggravated by TGF-β1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated Glutathione Peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced Ferroptosis process, which regulated YAP through a feedback loop. However, TGF-β1 annulled the repression of Ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-β1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of Ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of Ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI.

Cell biology; Functional aspects of cell biology; Pathophysiology.