Yiqi Wenyang Jiedu prescription promotes disulfidptosis of gastric cancer by reversing senescent cancer-associated fibroblasts

doi:10.4251/wjgo.v18.i3.115505

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World Journal of Gastrointestinal Oncology

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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 Gastrointest Oncol. Mar 15, 2026; 18(3): 115505
Published online Mar 15, 2026. doi: 10.4251/wjgo.v18.i3.115505

Yiqi Wenyang Jiedu prescription promotes disulfidptosis of gastric cancer by reversing senescent cancer-associated fibroblasts

Zi-Yu Kuang, Xiao-Yan Qin, Xin-Miao Wang, Xiao-Tong Song, Xiao-Yu Zhu, Jie Li

Zi-Yu Kuang, Xiao-Yan Qin, Xin-Miao Wang, Xiao-Yu Zhu, Jie Li, Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

Zi-Yu Kuang, Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China

Xiao-Tong Song, Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States

Co-first authors: Zi-Yu Kuang and Xiao-Yan Qin.

Co-corresponding authors: Xiao-Yu Zhu and Jie Li.

Author contributions: Kuang ZY and Qin XY were responsible for conceptualization, research design, investigation, data curation, and writing the original draft; Wang XM and Song XT were responsible for formal analysis, data visualization, validation, and reviewing & editing the manuscript. Kuang ZY and Qin XY contributed equally to this work as co-first authors. Li J and Zhu XY contributed equally as co-corresponding authors. They provided supervision, acquired funding, managed the project, and were responsible for critical review, commentary, and final approval of the manuscript.

Supported by National Natural Science Foundation of China, No. 82305347 and No. 82505704; Postdoctoral Fellowship Program of CPSF Under, No. GZC20233128; Basic Research Operating Expenses Special Fund of Central Public Welfare Research Institutes, No. ZZ16-XRZ-037; and China Academy of Chinese Medical Sciences Basic Scientific Research Business Fund Outstanding Young Scientific and Technological Talents Training Project, No. ZZ17-YQ-009.

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 Guang'anmen Hospital, China Academy of Chinese Medical Sciences (IACUC protocol number: IACUC-GAMH-2023-081-SQ); and approved by the Beijing Meidekona Laboratory Animal Welfare and Ethics Committee (No. MDKN-2024-124).

Conflict-of-interest statement: All 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: The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Corresponding author: Jie Li, MD, Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixiange Street, Xicheng District, Beijing 100053, China. qfm2020jieli@yeah.net

Received: October 21, 2025
Revised: November 18, 2025
Accepted: December 30, 2025
Published online: March 15, 2026
Processing time: 145 Days and 10.1 Hours

Abstract

BACKGROUND

Disulfidptosis is a specific form of cell death that occurs in cells with high SLC7A11 expression when glucose supply is insufficient. HAase, a senescence-associated phenotype secreted by senescent cancer-associated fibroblasts (senCAFs), can upregulate GLUT1 in tumor cells, thereby preventing disulfidptosis. Yiqi Wenyang Jiedu prescription (YWJP) is a Chinese herbal formula, and previous studies have shown that it can improve the clinical efficacy in the treatment of gastric cancer.

AIM

To investigate whether YWJP promotes gastric cancer cell disulfidptosis via HAase/GLUT1 pathway by reversing cancer-associated fibroblasts (CAFs) senescence and reducing HAase.

METHODS

CAFs were established using transforming growth factor-β1, and senCAFs were induced by H₂O₂. Senescence proportion was detected via β-galactosidase staining. ELISA and quantitative PCR measured interleukin-6 (IL-6), interleukin-8 (IL-8), hyaluronic acid, HAase, their mRNAs, NADP⁺/NADPH ratio, and disulfide bond levels. Western blot detected GLUT1 and disulfidptosis-related proteins. Propidium iodide (PI) staining quantified dead cells.

RESULTS

Based on previous research methods, we successfully established the CAFs and senCAFs models. The results showed that YWJP effectively reduced the proportion of senCAFs and simultaneously decreased the secretion of IL-6, IL-8, and HAase. Under HAase culture conditions, YWJP significantly downregulated the expression of GLUT1 and disulfidptosis-related proteins (CYFIP1, Rac1, ARP2, and ARP3), increased the disulfide bond level and the proportion of PI-positive cells in MKN45 cells, and thereby promoted disulfidptosis in MKN45 cells.

CONCLUSION

YWJP promotes disulfidptosis in MKN45 cells by reversing the proportion of senCAFs and reducing HAase secretion.

Keywords: Gastric cancer; Cancer-associated fibroblasts; Yiqi Wenyang Jiedu prescription; Disulfidptosis; Traditional Chinese medicine

Core Tip: This study demonstrates that Yiqi Wenyang Jiedu prescription (YWJP) promotes disulfidptosis in gastric cancer MKN45 cells. The mechanism involves YWJP reversing the senescence of cancer-associated fibroblasts (established by transforming growth factor-β1/H₂O₂), thereby reducing the secretion of HAase. The decrease in HAase leads to the downregulation of GLUT1 and key disulfidptosis-related proteins (CYFIP1, Rac1, ARP2, ARP3). This process increases intracellular disulfide bond levels and cell death, confirming that YWJP induces disulfidptosis via the HAase/GLUT1 pathway.