Extracts of Gleditsia sinensis Lam. thorn ameliorates ulcerative colitis through PPARγ/GPX4 pathway-mediated inhibition of enterocyte ferroptosis

doi:10.3748/wjg.120450

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Aug 28, 2026; 32(32): 120450
Published online Aug 28, 2026. doi: 10.3748/wjg.120450

Extracts of Gleditsia sinensis Lam. thorn ameliorates ulcerative colitis through PPARγ/GPX4 pathway-mediated inhibition of enterocyte ferroptosis

Zi-Yun Zhuo, Xiao-Ya Guo, Xiao-Ming Liu, Ming-Mei Shang, Shan Xue, Lei Peng, Zhi-Guo Guo

Zi-Yun Zhuo, Xiao-Ya Guo, Ming-Mei Shang, Shan Xue, Zhi-Guo Guo, Department of Gastroenterology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, Anhui Province, China

Xiao-Ming Liu, Department of Gastroenterology, Huaihe Hospital Affiliated to Henan University, Kaifeng 475000, Henan Province, China

Lei Peng, Department of Biological and Food Engineering, Suzhou University, Suzhou 234000, Anhui Province, China

Co-first authors: Zi-Yun Zhuo and Xiao-Ya Guo.

Co-corresponding authors: Lei Peng and Zhi-Guo Guo.

Author contributions: Zhuo ZY and Guo XY performed data acquisition and initial manuscript preparation as co-first authors; Zhuo ZY, Guo XY, Liu XM, and Shang MM conducted experimental procedures and data analysis; Xue S and Guo XY did visualization and verification; Peng L and Guo ZG did manuscript revision and result interpretation as co-corresponding authors; Guo ZG accomplished study design, data acquisition, funding procurement, and research supervision. All authors have read and approved the final manuscript.

Supported by National Natural Science Foundation of China, No. 82400621; Anhui Provincial Health Science and Technology Project, No. AHWJ2024Aa20059; Anhui Province Traditional Chinese Medicine Inheritance Innovation Project, No. 2024CCCX271; and Anhui Province Education Department Project, No. 2023jyxm1156.

Institutional animal care and use committee statement: All animal-related experimental procedures were reviewed and approved by the Ethics Committee of Suzhou Hospital of Anhui Medical University, No. KY-YJ-2024-006.

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: Technical appendix, statistical code, and dataset available from the corresponding author.

Corresponding author: Zhi-Guo Guo, MD, Professor, Department of Gastroenterology, Suzhou Hospital of Anhui Medical University, No. 616 Bianyangsan Road, Suzhou 234000, Anhui Province, China. guozhiguo@ahmu.edu.cn

Received: February 28, 2026
Revised: April 23, 2026
Accepted: June 22, 2026
Published online: August 28, 2026
Processing time: 158 Days and 14.4 Hours

Abstract

BACKGROUND

Extracts from Gleditsia sinensis thorns (EGST) have demonstrated anti-inflammatory effects. However, the involvement of ferroptosis and bile acid (BA) metabolism in their mechanisms remains unexplored.

AIM

To elucidate the mechanism by which EGST mitigate ulcerative colitis through suppression of enterocyte ferroptosis via the peroxisome proliferator-activated receptor gamma (PPARγ)/glutathione peroxidase 4 (GPX4) axis and modulation of BA metabolism.

METHODS

A murine ulcerative colitis model was established using 3% dextran sulfate sodium (DSS) and treated with EGST at varying doses over 7 days. In vitro, ferroptosis in Caco-2 cells was induced by erastin. EGST’s protective effects were evaluated through histopathological analysis, inflammatory mediator quantification, transmission electron microscopy, and mitochondrial membrane potential assessment. Network pharmacology was used to identify potential molecular targets, followed by molecular docking and dynamics simulations to validate ligand-receptor interactions. Additionally, targeted metabolomics employing liquid chromatography-mass spectrometry quantified over 50 BAs.

RESULTS

EGST significantly alleviated DSS-induced colitis by restoring colon length, reducing histopathological damage, and modulating cytokine levels (interleukin-6, tumor necrosis factor α, interleukin-10). In vitro, EGST countered erastin-induced alterations in glutathione, Fe²⁺, malondialdehyde, and reactive oxygen species, while also restoring mitochondrial membrane potential and mitochondrial ultrastructure. Network pharmacology analysis identified 45 overlapping targets, with core hub proteins including prostaglandin-endoperoxide synthase 2 and PPARγ. Molecular dynamics simulations confirmed stable binding of β-sitosterol, a bioactive compound in EGST, to the PPARγ ligand pocket. Mechanistic studies confirmed that EGST activate the PPARγ/GPX4 axis, upregulating PPARγ and GPX4 expression to levels comparable with the agonist rosiglitazone. Moreover, metabolomic analysis revealed a significant upregulation of taurohyodeoxycholic acid (THDCA), indicating that THDCA enhancement and BA metabolism regulation contribute to the improvement of colonic injury.

CONCLUSION

EGST significantly alleviate DSS-induced colitis by inhibiting intestinal epithelial cell ferroptosis through activation of the PPARγ/GPX4 signaling pathway and restoration of metabolic balance, particularly through the upregulation of THDCA.

Keywords: Ulcerative colitis; Extracts of Gleditsia sinensis Lam. thorn; Peroxisome proliferator-activated receptor gamma/ glutathione peroxidase 4; Bile acids; Ferroptosis

Core Tip: Extracts of Gleditsia sinensis Lam. thorn (EGST) ameliorates dextran sulfate sodium-induced ulcerative colitis. EGST inhibited the ferroptosis of erastin-induced Caco-2 cells. EGST regulates nitric oxide and reactive oxygen species inhibit lipid peroxidation. EGST activated the peroxisome proliferator-activated receptor gamma/glutathione peroxidase 4 signaling pathway and inhibit ferroptosis. We report for the first time that EGST alleviates colitis in mice by regulating taurohyodeoxycholic acid.