Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics

Jun-Fei Lu; Shang-Ping Xing; Xia Wei; Chun-Xia Yang; Gen-Shi Zhao; Xiao-Lin Ma; Xue-Mei Sun; Hong-Wei Guo; Zhi-Heng Su; Bin Fang; Jun Lin; Yan-Ying Liu; Dan Zhu

doi:10.3389/fphar.2024.1447560

Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics

Front Pharmacol. 2024 Sep 11:15:1447560. doi: 10.3389/fphar.2024.1447560. eCollection 2024.

Authors

Jun-Fei Lu^#^{1

2}, Shang-Ping Xing^#¹, Xia Wei¹, Chun-Xia Yang¹, Gen-Shi Zhao¹, Xiao-Lin Ma¹, Xue-Mei Sun¹, Hong-Wei Guo^{1

3}, Zhi-Heng Su¹, Bin Fang¹, Jun Lin¹, Yan-Ying Liu¹, Dan Zhu^{1

4

5

6}

Affiliations

¹ Pharmaceutical College, Guangxi Medical University, Nanning, China.
² Department of Pharmacy, College and Hospital of Stomatology, Guangxi Medical University, Nanning, China.
³ Key Laboratory of Longevity and Geriatric Diseases, Ministry of Education, Guangxi Medical University, Nanning, China.
⁴ Guangxi Key Laboratory for Bioactive Molecules Research and Evaluation, Nanning, China.
⁵ Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-value Utilization Engineering Research Center, Nanning, China.
⁶ Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, Nanning, China.

^# Contributed equally.

Abstract

Background: Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD.

Methods: Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated.

Results: HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1β, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD.

Conclusion: HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.

Keywords: 4-hydroxy-2(3H)-benzoxazolone; NF-κB; chronic alcoholic liver disease; glycerophospholipid metabolism; immune inflammation; metabolomics; oxidative stress; transcriptomics.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (82160734 and 81660106), Guangxi Major Science and Technology Project of China (GuikeAA22096021), the Guangxi Key Research and Development Program (GuiKeAB21196048), the Natural Science Foundation of Guangxi Zhuang Autonomous Region (2023GXNSFBA026237 and 2020GXNSFAA297114), Innovative Team for Traditional Chinese Medicinal Materials Quality of Guangxi (GZKJ2305), Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical University.