Helicobacter hepaticus promotes hepatic steatosis through CdtB-induced mitochondrial stress and lipid metabolism reprogramming

  • Nat Commun. 2025 Aug 26;16(1):7954. doi: 10.1038/s41467-025-63351-z.
Shanhao Jin  #  1  2 ,  Liqi Zhu  #  3  4 ,  Ruoyu Bao  1  2 ,  Linghan Yang  1  2 ,  Tinglong Zhuang  1  2 ,  Liyou Lian  5  6 ,  Tao Wang  1  2 ,  Jun Yin  1  2 ,  Shilei Zhang  7 ,  Lei Zhou  8 ,  Minghua Zheng  9  10 ,  Quan Zhang  11  12
Affiliations
  • 1. Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
  • 2. Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.
  • 3. Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China. [email protected].
  • 4. Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China. [email protected].
  • 5. MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 6. Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
  • 7. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
  • 8. Shanghai Immune Therapy Institute, Shanghai Jiaotong University School of Medicine-affiliated Renji Hospital, Shanghai, China.
  • 9. MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. [email protected].
  • 10. Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China. [email protected].
  • 11. Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, China. [email protected].
  • 12. Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China. [email protected].
  • # Contributed equally.
PMID: 40858606 DOI: 10.1038/s41467-025-63351-z
Abstract

Host-pathogen interaction influences many non-infectious diseases, including metabolic diseases. Helicobacter hepaticus (H. hepaticus) has been found in some metabolic dysfunction-associated steatotic liver disease (MASLD) patients, however, the causal link and underlying mechanisms remain unclear. Here we report that H. hepaticus Infection or overexpression of CdtB of H. hepaticus induces lipid deposition in hepatocytes, both in vivo and in vitro. Furthermore, we identify that CdtB translocates to mitochondria with the help of HSP90, interacts with ATP5A1, reduces mitochondrial respiratory complex V activity, damages mitochondria, and disrupts lipid metabolism. Mechanistically, CdtB-induced lipogenesis depends on the CdtB-mitochondrial ROS-mTORC1-SREBP1 axis and CdtB-mediated NONO expression to enhance nuclear localization of SREBP1 that promote the de novo fatty acid synthesis in the hepatocytes. Neutralization of CdtB significantly alleviates hepatic lipidosis in mice upon H. hepaticus Infection. Furthermore, the nucleic acid of H. hepaticus has been detected in the liver tissues of some patients with MASLD, which suggests a certain correlation between liver Infection with H. hepaticus and the occurrence and progression of MASLD. Our findings highlight the critical role of CdtB in the pathogenesis of H. hepaticus infection-induced hepatic lipidosis and its potential as a therapeutic target.

Products