Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2024; 30(8): 881-900
Published online Feb 28, 2024. doi: 10.3748/wjg.v30.i8.881
Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-on-chronic liver failure
Yu Zhang, Xiao-Ling Tian, Jie-Qun Li, Dong-Sheng Wu, Qiang Li, Bin Chen
Yu Zhang, Xiao-Ling Tian, Bin Chen, Department of Hepatology, Institute of Hepatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
Jie-Qun Li, Qiang Li, Department of Liver Transplant, Transplant Medical Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
Dong-Sheng Wu, Department of Surgery, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
Author contributions: Zhang Y and Tian XL performed experiments, analysed data and wrote the paper; Wu DS and Li Q performed experiments and analysed data; Li JQ and Chen B designed experiments, performed experiments and edited the paper.
Supported by the Domestic First-class Construction Disciplines of the Hunan University of Chinese Medicine; Postgraduate Research Innovation Program of Hunan Province, No. CX20220771; and Clinical MedTech Innovation Project of Hunan Province, No. 2021SK51415.
Institutional review board statement: The study protocol was approved by the Ethics Committee of the First Hospital of Hunan University of Chinese Medicine (No. HN-LL-SWST-15), and written informed consent was obtained from all participants.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no conflicts of interest that pertain to this work.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bin Chen, PhD, Chief Physician, Department of Hepatology, Institute of Hepatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, No. 95 Middle Shaoshan Road, Yuhua District, Changsha 410021, Hunan Province, China. chenbin0410@126.com
Received: October 8, 2023
Peer-review started: October 8, 2023
First decision: December 8, 2023
Revised: December 15, 2023
Accepted: January 23, 2024
Article in press: January 23, 2024
Published online: February 28, 2024

Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). However, the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.


To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.


Liver samples were collected from 16 healthy donors (HDs) and 17 advanced HBV-ACLF patients who were eligible for liver transplantation. The mitochondrial ultrastructure, metabolic characteristics, and immune microenvironment of the liver were assessed. More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.


Compared with HDs, there was extensive hepatocyte necrosis, immune cell infiltration, and ductular reaction in patients with ACLF. In patients, the liver suffered severe hypoxia, as evidenced by increased expression of hypoxia-inducible factor-1α. Swollen mitochondria and cristae were observed in the liver of patients. The number, length, width, and area of mitochondria were adaptively increased in hepatocytes. Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased, while anaerobic glycolysis was enhanced in patients with HBV-ACLF. These findings suggested that, to a greater extent, hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source. Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate, which stimulates peripheral monocyte infiltration into the liver. Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68+ HLA-DR+ macrophages and elevated levels of both interleukin-1β and transforming growth factor-β1 in their livers. The abundance of CD206+ CD163+ macrophages and expression of interleukin-10 decreased. The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.


The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling, leading to advanced HBV-ACLF. These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Keywords: Acute-on-chronic liver failure, Hypoxia-inducible factor-1α, Mitochondria, Metabolic phenotype, Immune cells

Core Tip: Our data were obtained from liver of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), whose mitochondrial function, metabolites, and immune microenvironment were less susceptible to any confounding factors caused by other failing organs. Widely infiltrating macrophages were originated from peripheral circulating monocytes in the liver of patients with HBV-ACLF. Mitochondrial oxidative phosphorylation was decreased, and anaerobic glycolysis was enhanced in patients with HBV-ACLF. Liver of patients made greater use of the extra-mitochondrial glycolytic pathway for providing energy. Bioenergetic alteration driven by hypoxia and mitochondrial dysfunction contribute to hepatic immune and metabolic remodeling, may leading to organ failure and poor clinical prognosis in patients with advanced HBV-ACLF.