Zhou J, Tian XL, Zhou YF, Zhou ZY, Tan NH, Chen B. Wenyang Jiedu Huayu Formula targets succinate metabolism to alleviate acute-on-chronic liver failure. World J Gastroenterol 2026; 32(37): 121244 [DOI: 10.3748/wjg.121244]
Corresponding Author of This Article
Bin Chen, MD, Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, No. 95 Shaoshan Middle Road, Yuhua District, Changsha 410007, Hunan Province, China. chenbin0410@126.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
research-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Oct 7, 2026; 32(37): 121244 Published online Oct 7, 2026. doi: 10.3748/wjg.121244
Wenyang Jiedu Huayu Formula targets succinate metabolism to alleviate acute-on-chronic liver failure
Jie Zhou, Xiao-Ling Tian, Yi-Fang Zhou, Zhuo-Yu Zhou, Nian-Hua Tan, Bin Chen
Jie Zhou, Nian-Hua Tan, Bin Chen, Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
Xiao-Ling Tian, Department of Traditional Chinese Medicine, School of Health and Medicine, China Three Gorges University, Yichang 443002, Hubei Province, China
Yi-Fang Zhou, Department of Gastroenterology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Changsha 410006, Hunan Province, China
Zhuo-Yu Zhou, Department of Otorhinolaryngology, Hunan Women and Children’s Hospital, Changsha 410208, Hunan Province, China
Co-corresponding authors: Nian-Hua Tan and Bin Chen.
Author contributions: Zhou J performed the experiments, analyzed the data, and wrote the manuscript; Tian XL, Zhou YF, and Zhou ZY performed the experiments and analyzed the data; Tan NH and Chen B designed and coordinated the study as co-corresponding authors. All authors approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 82575008; Chinese Medicine Advantageous Disease (Clinical Evidence-Based Capacity Enhancement) Project of the National Administration of Traditional Chinese Medicine, No. czxm-kyb-2025001; Hunan Provincial Natural Science Foundation of China, No. 2026JJ30167 and No. 2026JJ50326; University-Hospital Joint Fund Project of Hunan University of Chinese Medicine, No. 2024XYLH343; and Hunan Provincial Postgraduate Research Innovation Project, No. 2024CX018.
Institutional animal care and use committee statement: This study was approved by the Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine, No. ZYFY202503313.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Corresponding author: Bin Chen, MD, Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, No. 95 Shaoshan Middle Road, Yuhua District, Changsha 410007, Hunan Province, China. chenbin0410@126.com
Received: March 20, 2026 Revised: April 25, 2026 Accepted: June 30, 2026 Published online: October 7, 2026 Processing time: 165 Days and 17 Hours
Abstract
BACKGROUND
Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by acute hepatic decompensation and high short-term mortality. Although Wenyang Jiedu Huayu Formula (WYJD) has demonstrated therapeutic efficacy for alleviating liver injury and modulating immune inflammation, whether its hepatoprotective effects involve targeting succinate metabolism remains unclear.
AIM
To investigate whether WYJD exerts therapeutic effects in ACLF by targeting succinate metabolism and to elucidate the underlying molecular mechanisms.
METHODS
ACLF rat model was prepared by sensitization using bovine serum albumin, followed by D-galactosamine/lipopolysaccharide challenge. Animals were assigned to normal control, Model, WYJD, and WYJD plus succinate dehydrogenase (SDH) inhibitor groups. Therapeutic efficacy was evaluated using hepatic histopathology and inflammatory cytokine profiling. Succinate metabolism-related molecular changes were systematically analyzed using targeted energy metabolomics, biochemical enzyme activity assays, western blotting, and reverse transcription quantitative polymerase chain reaction. Mitochondrial ultrastructure was examined using transmission electron microscopy. Intrahepatic macrophage infiltration was assessed using immunofluorescence staining.
RESULTS
WYJD treatment markedly attenuated hepatic necrosis and inflammatory cell infiltration in ACLF rat models. Metabolomic analysis revealed succinate accumulation and tricarboxylic acid cycle dysfunction in the ACLF liver tissues, which were effectively reversed by WYJD. Mechanistically, WYJD upregulated SDH activity and expression of its catalytic subunits SDHA/B, facilitating succinate-to-fumarate conversion and reducing succinate levels, thereby suppressing downstream hypoxia-inducible factor-1α expression. In addition, WYJD improved mitochondrial ultrastructure, restored ATP content, and reduced CD68+ macrophage infiltration in liver. These beneficial effects were partially abolished by SDH inhibition.
CONCLUSION
WYJD ameliorated ACLF by acting partly through SDH to clear accumulated succinate and suppress hypoxia-inducible factor-1α-mediated inflammation, suggesting succinate metabolism as a potential therapeutic target.
Core Tip: This study demonstrated that Wenyang Jiedu Huayu Formula (WYJD) ameliorated acute-on-chronic liver failure by targeting succinate metabolism. WYJD acts partly through succinate dehydrogenase to clear accumulated succinate and suppress hypoxia-inducible factor-1α signaling, thereby correcting energy metabolic disturbances and attenuating macrophage-mediated inflammation. These findings suggested that succinate metabolism can be a potential therapeutic target in acute-on-chronic liver failure, and the study provided mechanistic insights supporting the clinical application of WYJD from a metabolic-immune perspective.
