Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 27, 2024; 16(7): 1051-1066
Published online Jul 27, 2024. doi: 10.4254/wjh.v16.i7.1051
Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism
Xiao-Li Mei, Shu-Yi Wu, Si-Lan Wu, Xiao-Lin Luo, Si-Xing Huang, Rui Liu, Zhe Qiang
Xiao-Li Mei, Si-Lan Wu, Xiao-Lin Luo, Si-Xing Huang, Zhe Qiang, Department of Pharmacology and Toxicology, Sichuan-Chongqing Joint Key Laboratory of New Chinese Medicine Creation Laboratory, Chongqing Academy of Chinese Materia Medica, Chongqing 400061, China
Shu-Yi Wu, Zhe Qiang, College of Chinese Medicine, Chongqing College of Traditional Chinses Medicine, Chongqing 402760, China
Rui Liu, Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
Zhe Qiang, College of Pharmacy, Chongqing Medical University, Chongqing 400010, China
Co-first authors: Xiao-Li Mei and Shu-Yi Wu.
Co-corresponding authors: Rui Liu and Zhe Qiang.
Author contributions: Qiang Z and Liu R designed the research; Mei XL and Wu SY performed the research; Wu SL, Luo XL and Huang SX analyzed the data; Qiang Z and Liu R wrote the paper. All authors have read and approved the final manuscript. Mei XL and Wu SY contributed equally to this work as co-first authors. The reason for designating co-first authors is that Mei XL and Wu SY played indispensable roles in the experimental data interpretation and manuscript preparation. Qiang Z and Liu R have the same contribution to this work as co-corresponding authors. The reason for designating co-corresponding authors is that the collaboration between Qiang Z and Liu R is crucial for the experimental design and publication of this manuscript. This designation of co-corresponding authors ensures effective communication and management of post-submission matters, ultimately enhancing the paper's quality and reliability.
Supported by Chongqing Fundamental Research Funds, No. jbky20210001; Key Programs of Technological Innovation and Application Development of Chongqing, China, No. cstc2021jscx-dxwtBX0016; Natural Science Foundation of Chongqing, No. cstc2021jcyj-msxmX0793; Science and Technology Project in Social Livelihood of Bishan District, Chongqing, China, No. BSKJ0078 and No. BSKJ0075; and Performance Incentive-oriented Project of Chongqing, No. jxjl20220007.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Chongqing Academy of Chinese Materia Medica, approval No. CTCM 2022YN012.
Conflict-of-interest statement: All authors have no conflicts of interest to declare.
Data sharing statement: The data that support the findings of this study are available from the corresponding author at qiangzhe@cqctcm.edu.cn upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
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: Zhe Qiang, MD, Associate Professor, Department of Pharmacology and Toxicology, Sichuan-Chongqing Joint Key Laboratory of New Chinese Medicine Creation Laboratory, Chongqing Academy of Chinese Materia Medica, No. 34 Nanshan Road, Huangjueya, Nan'an District, Chongqing 400061, China. qiangzhe@cqctcm.edu.cn
Received: April 15, 2024
Revised: May 23, 2024
Accepted: June 11, 2024
Published online: July 27, 2024
Processing time: 101 Days and 18.4 Hours
Abstract
BACKGROUND

The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear.

AIM

To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation.

METHODS

A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.

RESULTS

MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones.

CONCLUSION

MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

Keywords: Hepatic steatosis; Inflammation; Sex hormone metabolism; Male hormone; Phosphatase and tensin homolog deleted on chromosome ten

Core Tip: In this study, the modified Xiaoyao San (MXS) formula was found can alleviated inflammation and hepatic steatosis in nonalcoholic steatohepatitis (NASH) by suppressing male hormone metabolism and modulating inflammation/lipid metabolism-related signaling and factors. It suggested that the regulation of sex hormone metabolism and associated signaling could be new avenues for mechanistic research on NASH and for early diagnosis and treatment. This study offers substantial evidence for the therapeutic potential of MXS in NASH and makes a valuable contribution to the development of new drugs for this condition.