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  3. Manganese inhibits HBV transcription and promotes HBsAg degradation at non-toxic levels

Manganese inhibits HBV transcription and promotes HBsAg degradation at non-toxic levels

  • Int J Biol Macromol. 2024 Sep 17;280(Pt 2):135764. doi: 10.1016/j.ijbiomac.2024.135764.
Yong Zhang 1,  Shaowei Han 2,  Yuanyuan Li 2,  Yuting Zhou 3,  Mengdan Sun 2,  Mingna Hu 3,  Chengcai Zhou 2,  Lu Lin 4,  Jianfeng Lan 2,  Xing Lu 2,  Qinqin Zhang 5,  Lingyun Liu 6,  Junfei Jin 7
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China. Electronic address: zhangyong@glmc.edu.cn.
  • 2 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China.
  • 3 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; School of Pharmacy, Xinjiang Medical University, Urumqi 830011, Xinjiang, China.
  • 4 Clinical Medical College, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China.
  • 5 Department of Thyroid and Breast Surgery, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541002, Guangxi, China.
  • 6 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; Department of Hepatobiliary and Pancreatic Surgery, Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China.
  • 7 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China; Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China. Electronic address: junfeijin@glmc.edu.cn.
PMID: 39299429 DOI: 10.1016/j.ijbiomac.2024.135764
Abstract

Chronic hepatitis B virus (HBV) Infection continues to pose a significant global health challenge. However, therapeutic measures for a cure are lacking in clinical practice. Manganese, an essential trace element, has garnered attention due to its potential to activate innate immune pathways and its significant role in Antiviral and antitumor immunity. Yet, the specific impact of manganese on chronic hepatitis B has been largely unexplored. Our research reveals that manganese substantially inhibits HBV replication in hepatocellular carcinoma cells at non-toxic levels. This suppression occurs independently of well-known anti-HBV innate immune pathways, such as the cGAS-STING pathway. Mechanistically, manganese decreases HBV transcription by diminishing the levels of liver-specific transcription factors. Furthermore, it activates the mTOR pathway, enhancing HBsAg ubiquitination through the upregulation of the ubiquitin Ligase β-TrCP and increasing Proteasome activity via the augmentation of its subunits, leading to a ubiquitin-dependent degradation of HBsAg. Significantly, our study also uncovers a notable clinical correlation between manganese levels and chronic hepatitis B Infection. These findings position manganese as a critical element in diminishing HBV replication, offering a new direction in the management of chronic hepatitis B.

Keywords

HBV transcription; HBsAg; Manganese; Ubiquitin-proteasome system; mTOR.

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