Yes-associated protein inhibition ameliorates liver fibrosis and acute and chronic liver failure by decreasing ferroptosis and necroptosis
Wen Zhao,
Miao Lei,
Jinfeng Li,
Hailin Zhang,
Hongkun Zhang,
Yuxin Han,
Zhiwei Ba,
Manli Zhang,
Dongdong Li,
Chuanmiao Liu
Affiliations
Wen Zhao
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Miao Lei
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Jinfeng Li
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Hailin Zhang
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Hongkun Zhang
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Yuxin Han
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Zhiwei Ba
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Manli Zhang
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Dongdong Li
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China
Chuanmiao Liu
Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China; Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China; Key Laboratory of Infection and Immunity of Anhui Province, China; Corresponding author. Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China.
Background/aims: This study aims to determine which cell death modes contribute most in the progression of cirrhosis and acute-on-chronic liver failure (ACLF), and to investigate whether Yes associated protein (YAP) affects the disease process by regulating cell death. Materials and methods: 30C57BL/6 male mice were divided into five groups: control, carbon tetrachloride (CCl4)-induced liver fibrosis model, CCl4+verteporfin, CCl4+lipopolysaccharides (LPS) combined with the D-(+)-Galactosamine (LPS/D-GalN)-induced ACLF model, and ACLF + verteporfin. Patients with chronic hepatitis B (CHB), hepatitis B virus (HBV) related liver cirrhosis or ACLF were enrolled. Histology, immunohistochemistry, transmission electron microscopy, Western blot and ELISA were conducted to assess the roles of YAP and cell death in liver cirrhosis and ACLF, and to explore the effect of YAP inhibition on cell deaths. Results: YAP was markedly increased in mice with liver fibrosis and ACLF, along with ferroptosis and necroptosis. Furthermore, YAP inhibition significantly suppressed fibrosis in CCl4-mediated liver fibrosis and ACLF-associated liver injury. Notably, CCl4 induced up-regulation of ACSL4 and RIPK3 and down-regulation of SLC7A11, key factors in ferroptosis and necroptosis. This was significantly abrogated by verteporfin treatment. Similar changes in ferroptosis and necroptosis were found in ACLF and ACLF + verteporfin groups. Consistent with the above findings in mice, we found that plasma YAP levels were gradually increased with the development of HBV-related liver fibrosis and ACLF. Conclusion: Ferroptosis and necroptosis are involved in the development of liver cirrhosis and ACLF. Inhibition of YAP improved liver fibrosis and liver damage in ACLF through a reduction in ferroptosis and necroptosis. Our findings may help better understanding the role of YAP in liver fibrosis and ACLF.
