Zhang XF, Lv GH, An SJ, Yang XR, Guo WZ, Yu CY, Zhu CH. Dysregulation of the HIF-1α/BNIP3 axis links defective mitophagy to glycolytic reprogramming in a rat model of gastric precancerogenesis. World J Gastrointest Oncol 2026; 18(4): 117815 [DOI: 10.4251/wjgo.v18.i4.117815]
Corresponding Author of This Article
Cheng-Hui Zhu, MD, Associate Chief Physician, Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Liaoning Provincial Institute of Traditional Chinese Medicine, No. 60 Huanghebei Street, Huanggu District, Shenyang 110031, Liaoning Province, China. zhuchenghui2005@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Apr 15, 2026 (publication date) through Apr 11, 2026
Times Cited of This Article
Times Cited (0)
Journal Information of This Article
Publication Name
World Journal of Gastrointestinal Oncology
ISSN
1948-5204
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Share the Article
Zhang XF, Lv GH, An SJ, Yang XR, Guo WZ, Yu CY, Zhu CH. Dysregulation of the HIF-1α/BNIP3 axis links defective mitophagy to glycolytic reprogramming in a rat model of gastric precancerogenesis. World J Gastrointest Oncol 2026; 18(4): 117815 [DOI: 10.4251/wjgo.v18.i4.117815]
Xin-Fang Zhang, Shu-Jian An, Xi-Ran Yang, Wen-Zhao Guo, Chen-Yang Yu, Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, Liaoning Province, China
Guan-Hua Lv, Cheng-Hui Zhu, Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Liaoning Provincial Institute of Traditional Chinese Medicine, Shenyang 110031, Liaoning Province, China
Author contributions: Zhang XF performed the experiments, analyzed the data, and wrote the original draft of the manuscript; Lv GH and Zhu CH conceived and designed the study, supervised the project, and critically revised the manuscript; An SJ, Yang XR, Guo WZ and Yu CY contributed to the animal experiments and sample collection; all authors have read and approved the final version of the manuscript.
Supported by Joint Program of the Science and Technology Plan of Liaoning Province (Natural Science Foundation – General Program), No. 2024012225-JH4/4800.
Institutional animal care and use committee statement: This animal study was reviewed and approved by the Ethics Committee of Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine (No. LZYY250203).
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
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: No additional data are available.
Corresponding author: Cheng-Hui Zhu, MD, Associate Chief Physician, Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Liaoning Provincial Institute of Traditional Chinese Medicine, No. 60 Huanghebei Street, Huanggu District, Shenyang 110031, Liaoning Province, China. zhuchenghui2005@163.com
Received: December 16, 2025 Revised: January 27, 2026 Accepted: February 26, 2026 Published online: April 15, 2026 Processing time: 112 Days and 23.7 Hours
Abstract
BACKGROUND
Chronic atrophic gastritis is a common gastric disorder frequently accompanied by precancerous lesions, including intestinal metaplasia and dysplasia. Progression of these lesions represents a critical stage in gastric carcinogenesis. Hypoxia-inducible factor 1-alpha (HIF-1α) and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) are key regulators of cellular hypoxia responses and mitophagy, while metabolic reprogramming toward glycolysis is closely associated with gastric mucosal transformation. We hypothesized that dysregulation of HIF-1α/BNIP3 signaling promotes precancerous lesions of gastric cancer (PLGC) development through coordinated alterations in mitophagy and glycolytic metabolism.
AIM
To determine dynamic changes in HIF-1α/BNIP3 signaling and investigate mitophagy-glycolysis interactions during PLGC development in rats.
METHODS
Eighty male Sprague-Dawley rats were randomly assigned to normal and model groups. A PLGC model was established using a comprehensive induction method. Eight rats per group were sacrificed at weeks 4, 10, 16, 22, and 28. Gastric histopathology was evaluated by hematoxylin and eosin staining. Immunofluorescence assessed HIF-1α and BNIP3 expression in gastric antrum tissue. Quantitative real-time polymerase chain reaction and western blotting were used to assess the expression of mitophagy-related and glycolysis-related genes and proteins.
RESULTS
As time progressed, gastric mucosa in the model group gradually developed inflammation, atrophy, intestinal metaplasia, and dysplasia. In gastric antrum tissue, HIF-1α protein and mRNA expression continuously increased. The expression of mitophagy-related markers, including BNIP3, Beclin1, and microtubule-associated protein 1 light chain 3, initially increased but subsequently declined, whereas sequestosome 1 expression showed an opposite trend. Regarding metabolic alterations, cytochrome C oxidase subunit 4 expression exhibited a mild decrease from week 16, while hexokinase 2 and lactate dehydrogenase A protein and mRNA expression significantly increased from week 22 onward.
CONCLUSION
HIF-1α/BNIP3 signaling dynamically regulates mitophagy and glycolysis during PLGC progression; appropriate HIF-1α is protective, whereas sustained overexpression induces autophagy dysfunction and metabolic imbalance.
Core Tip: In the hypoxic microenvironment of gastric precancerogenesis, the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α) is a master regulator of both mitophagy and glycolysis. Our study reveals that sustained overexpression of HIF-1α during the progression of precancerous gastric lesions drives autophagic failure via the BCL2/adenovirus E1B 19 kDa interacting protein 3 pathway. This defective autophagy is tightly linked to a subsequent metabolic switch, characterized by the late-stage activation of glycolysis. This work identifies the dysregulation of the HIF-1α/BCL2/adenovirus E1B 19 kDa interacting protein 3 axis as a key event linking failed mitochondrial quality control to the pro-tumorigenic glycolytic reprogramming in the stomach.
