USP7 upregulated by TGF-β1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury
Hong Lv,
Jing Yu,
Xingjia Qian,
Jun Shu,
Qiuhong Qian,
Luhong Shen,
Dongfang Shi,
Zhengzheng Tao,
Guiqin Fan,
Bufeng Zhuang,
Bing Lu
Affiliations
Hong Lv
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Jing Yu
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Xingjia Qian
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Jun Shu
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Qiuhong Qian
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Luhong Shen
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Dongfang Shi
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Zhengzheng Tao
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China
Guiqin Fan
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China; Soochow University School of Medicine, Suzhou, Jiangsu Province 215031, P.R. China
Bufeng Zhuang
Department of Thoracic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, P.R. China; Corresponding author
Bing Lu
Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Affliated to Nanjing University of Chinese Medicine, Taicang, Jiangsu Province 215499, P.R. China; Corresponding author
Summary: 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.
