TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling
Wantong Su,
Weicheng Gao,
Rui Zhang,
Qi Wang,
Lei Li,
Qingfa Bu,
Zibo Xu,
Zheng Liu,
Mingming Wang,
Yaqing Zhu,
Guoping Wu,
Haoming Zhou,
Xun Wang,
Ling Lu
Affiliations
Wantong Su
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Weicheng Gao
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China
Rui Zhang
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Qi Wang
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Lei Li
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Qingfa Bu
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Zibo Xu
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Zheng Liu
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Mingming Wang
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
Yaqing Zhu
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.
Guoping Wu
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital, Nanjing Medical University, Nanjing, China.
Haoming Zhou
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Corresponding authors. Addresses: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Nanjing, China. Tel.: +86-25-68303947.
Xun Wang
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Corresponding authors. Addresses: Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University, Nanjing, China. Tel.: +86-25-68303947.
Ling Lu
Department of Plastic and Cosmetic Surgery of the Affiliated Friendship Plastic Surgery Hospital & Hepatobiliary Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
Background & Aims: Oxidative stress-mediated ferroptosis and macrophage-related inflammation play an important role in various liver diseases. Here, we explored if and how hepatocyte ferroptosis regulates macrophage stimulator of interferon genes (STING) activation in the development of spontaneous liver damage, fibrosis, and tumorigenesis. Methods: We used a transforming growth factor-beta-activated kinase 1 (TAK1) deficiency-induced model of spontaneous liver damage, fibrosis, and tumorigenesis to investigate hepatocyte ferroptosis and its impact on macrophage STING signalling. Primary hepatocytes and macrophages were used for in vitro experiments. Results: Significant liver injury and increased numbers of intrahepatic M1 macrophages were found in hepatocyte-specific TAK1-deficient (TAK1ΔHEP) mice, peaking at 4 weeks and gradually decreasing at 8 and 12 weeks. Meanwhile, activation of STING signalling was observed in livers from TAK1ΔHEP mice at 4 weeks and had decreased at 8 and 12 weeks. Treatment with a STING inhibitor promoted macrophage M2 polarisation and alleviated liver injury, fibrosis, and tumour burden. TAK1 deficiency exacerbated liver iron metabolism in mice with a high-iron diet. Moreover, consistent with the results from single-cell RNA-Seq dataset, TAK1ΔHEP mice demonstrated an increased oxidative response and hepatocellular ferroptosis, which could be inhibited by reactive oxygen species scavenging. Suppression of ferroptosis by ferrostatin-1 inhibited the activation of macrophage STING signalling, leading to attenuated liver injury and fibrosis and a reduced tumour burden. Mechanistically, increased intrahepatic and serum levels of 8-hydroxydeoxyguanosine were detected in TAK1ΔHEP mice, which was suppressed by ferroptosis inhibition. Treatment with 8-hydroxydeoxyguanosine antibody inhibited macrophage STING activation in TAK1ΔHEP mice. Conclusions: Hepatocellular ferroptosis-derived oxidative DNA damage promotes macrophage STING activation to facilitate the development of liver injury, fibrosis, and tumorigenesis. Inhibition of macrophage STING may represent a novel therapeutic approach for the prevention of chronic liver disease. Impact and implications: The precise mechanism by which hepatocyte ferroptosis regulates macrophage STING activation in the progression of liver damage, fibrosis, and tumorigenesis remains unclear. Herein, we show that deletion of TAK1 in hepatocytes caused oxidative stress-mediated ferroptosis and macrophage-related inflammation in the development of spontaneous liver injury, fibrosis, and hepatocellular carcinoma.
