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World J Gastroenterol. Jul 7, 2026; 32(25): 118842
Published online Jul 7, 2026. doi: 10.3748/wjg.118842
FOLH1 as a novel biomarker for risk stratification in gastric intestinal metaplasia
Shan He, Xiao-Fei Guo, Yuan Wang, Jian-Qi Bai, Jian-Peng Wang, Jun-He Shi, Yang-Yi Shi, Jing Yuan, Wei Wei, Yang Yang, Xiao-Hua Shi, Yao Feng, Xia Ding, Wei Gao, Dan Lu, Wei-Xun Zhou, Ping Zhang
Shan He, Pharmacological Laboratory, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100016, China
Xiao-Fei Guo, Yuan Wang, Jian-Qi Bai, Jian-Peng Wang, Yang-Yi Shi, Ping Zhang, Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100016, China
Jun-He Shi, NMPA Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
Jing Yuan, Department of Pathology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
Wei Wei, Yang Yang, Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100016, China
Xiao-Hua Shi, Wei-Xun Zhou, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
Yao Feng, Dan Lu, Institute of Systems Biomedicine, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China
Xia Ding, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
Wei Gao, Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
Co-first authors: Shan He and Xiao-Fei Guo.
Co-corresponding authors: Wei-Xun Zhou and Ping Zhang.
Author contributions: He S write the original draft; Guo XF performed the methodology and data analysis; Bai JQ, Wang JP, Feng Y, Lu D, and Shi YY performed the methodology; Shi JH and Wang Y performed the validation; Yuan J, Ding X, Gao W, Yang Y, Wei W, Shi XH, Lu D, and Zhou WX contributed the supervision; Zhang P contributed the supervision and funding acquisition; He S and Guo XF equally contributed to this manuscript as they are co-first authors; Zhang P and Zhou WX equally contributed to corresponding this manuscript, as they are co-corresponding authors.
Supported by the China Academy of Chinese Medical Sciences, No. WJYY-XZKT-2023-07; and the National Key Research and Development Program of China, No. 2023YFC3503600.
Institutional review board statement: All studies were approved by the Ethics Committee of Wangjing Hospital, China Academy of Chinese Medical Sciences (No. WJEC-KT-2023-046-P001).
Informed consent statement: All patients signed the informed consent statement.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: Not applicable.
Corresponding author: Ping Zhang, MD, Full Professor, Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6 Huajiadi Street, Chaoyang District, Beijing 100016, China.
pinglele@sina.com
Received: January 13, 2026
Revised: February 24, 2026
Accepted: March 25, 2026
Published online: July 7, 2026
Processing time: 169 Days and 6.2 Hours
BACKGROUND
Gastric intestinal metaplasia (GIM) is a precancerous condition associated with gastric cancer (GC). However, biomarkers that predict progression from GIM to GC remain unclear.
AIM
To investigate the potential of FOLH1 as a novel tissue-based biomarker for identifying patients with GIM at high risk of progression to GC.
METHODS
This single-center retrospective cohort study was conducted at Wangjing Hospital and included 68 patients diagnosed with GIM. GIM samples were obtained sequentially from the antrum using endoscopic biopsies. Patients were assigned to the progressive group (P) if they developed high-grade intraepithelial neoplasia, intramucosal carcinoma, or adenocarcinoma during the 5-year follow-up; patients whose GIM remained stable were assigned to the non-progression group (N). A subset of 8 patients (4 from group P and 4 from group N) was used to identify potential biomarkers using differentially expressed genes and weighted gene correlation network analysis based on digital spatial profiling. The remaining 60 patients were used to validate candidate biomarkers using histologic evaluation, immunohistochemical staining, and immunofluorescent staining.
RESULTS
In the 8-patient discovery cohort, FOLH1 expression was significantly decreased in the epithelium of patients in group P compared with those in group N. In the 60-patient validation cohort, FOLH1 was a reliable biomarker for predicting malignant transformation from GIM to GC, with a sensitivity of 0.967 and a specificity of 1.000. Using Youden’s index, the optimal diagnostic cutoff value for FOLH1 was 0.302, corresponding to an integral optical density of 31.46.
CONCLUSION
FOLH1 may serve as a tissue-based biomarker for predicting progression from GIM to GC.
Core Tip: In this study, digital spatial profiling was used to identify differentially expressed genes between progressive and nonprogressive gastric intestinal metaplasia (GIM). Among 14 candidate genes, FOLH1 showed the most significant difference. Validation in 60 patients using immunohistochemical and immunofluorescent staining confirmed that low FOLH1 expression strongly predicted progression, with excellent 4 diagnostic accuracy, establishing FOLH1 as a novel biomarker for risk stratification in GIM.
