Yiwei Xiaoyu granules mitigate spasmolytic polypeptide-expressing metaplasia-associated gastric mucosal damage by regulating WFDC2 and the miRNA-7/circRNA network

doi:10.4251/wjgo.118787

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World Journal of Gastrointestinal Oncology

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1948-5204

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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 Gastrointest Oncol. Jul 15, 2026; 18(7): 118787
Published online Jul 15, 2026. doi: 10.4251/wjgo.118787

Yiwei Xiaoyu granules mitigate spasmolytic polypeptide-expressing metaplasia-associated gastric mucosal damage by regulating WFDC2 and the miRNA-7/circRNA network

Jin-Wei Zhang, Yan-Ping Li, Hang Ma, Min Duan, He-Lin Pan, Ying-Yue Xu, Wan-Qun Chen

Wan-Qun Chen, Ying-Yue Xu, He-Lin Pan, Min Duan, Yan-Ping Li, Department of Gastroenterology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400000, China

Hang Ma, College of Pharmaceutical Sciences, Southwest University, Chongqing 400000, China

Jin-Wei Zhang, Chongqing General Hospital, Chongqing University, Chongqing 400000, China

Co-corresponding authors: Yan-Ping Li and Jin-Wei Zhang.

Author contributions: Chen WQ and Xu YY performed the animal experiments, histological evaluation, molecular assays, and data acquisition; Pan HL and Duan M assisted with immunofluorescence, fluorescence in situ hybridization, and image quantification; Ma H participated in study design, herbal formulation quality control, and interpretation of pharmacological data; Li YP contributed to the conception of the study, traditional Chinese medicine syndrome modeling, and interpretation of clinical relevance; Zhang JW conceived and supervised the study, coordinated the overall experimental design, and critically revised the manuscript for important intellectual content. All authors reviewed and approved the final manuscript. The designation of two co-corresponding authors is based on their complementary contributions and shared responsibility for the study. Li YP contributed to the study conception, traditional Chinese medicine syndrome modeling, and interpretation of clinical relevance, providing important academic guidance. Zhang JW conceived and supervised the study, coordinated the overall experimental design, and critically revised the manuscript. Both authors were actively involved in manuscript revision and will jointly take responsibility for correspondence.

AI contribution statement: ChatGPT was used for limited language editing and wording suggestions during manuscript preparation. AI tools were used only for language polishing, grammar improvement, and writing assistance. No AI tool was used for data analysis.

Supported by National Natural Science Foundation of China, No. 81904175; Chongqing Technological Innovation and Applied Development Special Project, No. CSTB2022TIAD-KPX0187; and Young Scholars Cultivation Program of the Spleen and Stomach Diseases Branch, China Association of Chinese Medicine, No. 202557-001.

Institutional animal care and use committee statement: All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Chongqing Traditional Chinese Medicine Hospital (Approval No. 2020-DWKY-01), in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

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/or analyzed during the current study are available from the corresponding author on reasonable request.

Corresponding author: Jin-Wei Zhang, PhD, Chongqing General Hospital, Chongqing University, No. 118 Xingguang Avenue, Yubei District, Chongqing 400000, China. jinwei.zhang@cqu.edu.cn

Received: January 12, 2026
Revised: February 11, 2026
Accepted: March 27, 2026
Published online: July 15, 2026
Processing time: 183 Days and 10 Hours

Abstract

BACKGROUND

Gastric cancer develops through a sequence of atrophy, metaplasia, and dysplasia. Spasmolytic polypeptide-expressing metaplasia (SPEM) is a pivotal precancerous lesion associated with inflammation and noncoding RNA dysregulation. In traditional Chinese medicine (TCM), these pathological changes overlap with spleen-stomach deficiency syndrome (SSDS). Yiwei Xiaoyu granules (YWXY), a classical TCM formula, have demonstrated clinical benefit in chronic atrophic gastritis, yet their mechanistic actions in SPEM combined with SSDS remain unclear.

AIM

To investigate the protective effects and mechanisms of YWXY in a tamoxifen-induced SPEM and SSDS composite model.

METHODS

A mouse model of tamoxifen-induced SPEM, with or without SSDS, was established. The effects of YWXY on gastric mucosa were evaluated by histological scoring, quantitative polymerase chain reaction (qPCR), and fluorescence in situ hybridization (FISH). Key molecular endpoints included inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α], the miR-7a-5p/Cdr1as axis, and the metaplastic marker WFDC2. Statistical analysis was performed using two-way analysis of variance followed by Tukey’s multiple comparisons.

RESULTS

YWXY exhibited time-dependent modulation of IL-1β, normalizing its expression at day 15 and suppressing persistent elevation at day 30. TNF-α overexpression in SPEM was significantly reduced by YWXY at both time points. Cdr1as downregulation in pathological groups was partially reversed by YWXY, while miR-7a-5p suppression in SSDS and SPEM + SSDS was restored toward baseline. WFDC2 induction in both SPEM and SSDS was significantly attenuated by YWXY, confirmed by qPCR and FISH. These findings indicate coordinated regulation of inflammatory cytokines, ncRNA networks, and metaplastic markers.

CONCLUSION

YWXY alleviates gastric mucosal injury in combined SPEM and SSDS by regulating IL-1β and TNF-α, restoring the miR-7a-5p/Cdr1as axis, and suppressing WFDC2 expression.

Keywords: Spasmolytic polypeptide-expressing metaplasia; Spleen-stomach deficiency syndrome; Yiwei Xiaoyu granules; miR-7a-5p/Cdr1as; WFDC2

Core Tip: Spasmolytic polypeptide-expressing metaplasia (SPEM) represents a key precancerous stage of gastric carcinogenesis and frequently coexists with spleen-stomach deficiency syndrome (SSDS) in clinical practice. Using a combined tamoxifen-induced SPEM and SSDS mouse model, we demonstrate that Yiwei Xiaoyu granules exert sustained protective effects on gastric mucosa. Yiwei Xiaoyu granules bidirectionally regulates inflammatory cytokines, restores the miR-7a-5p/Cdr1as axis, and suppresses WFDC2 induction, thereby linking syndrome-based intervention with molecular mechanisms of gastric precancerous lesions.