Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2025; 31(22): 105157
Published online Jun 14, 2025. doi: 10.3748/wjg.v31.i22.105157
N6-methyladenosine reader IGF2BP2 regulates NIPSNAP1-mediated mitophagy and mitochondrial dynamics to alleviate hepatic ischemia-reperfusion injury
Shan-Shan Guo, Yan Zhao, Yan Hu, Xin-Ying Wang, Xu-Zi Zhao, Pei-Yan Zhong, Qin-Rong Luan, Zhe-Cheng Wang, Ji-Hong Yao
Shan-Shan Guo, Yan Hu, Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian 116044, Liaoning Province, China
Yan Zhao, Xin-Ying Wang, Qin-Rong Luan, Zhe-Cheng Wang, Ji-Hong Yao, Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Xu-Zi Zhao, Pei-Yan Zhong, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116044, Liaoning Province, China
Co-first authors: Shan-Shan Guo and Yan Zhao.
Co-corresponding authors: Zhe-Cheng Wang and Ji-Hong Yao.
Author contributions: Guo SS and Zhao Y contributed equally to this article, they are the co-first authors of this manuscript; Guo SS, Wang ZC, and Yao JH designed the study; Guo SS, Hu Y, Zhao Y, and Zhong PY performed the experiments; Guo SS, Wang XY, Zhao XZ, and Luan QR analyzed the data; Guo SS and Wang ZC drafted the manuscript; Wang ZC and Yao JH contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82200658.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Dalian Medical University, approval No. AEE20004.
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: All the data obtained in the current study are available from the corresponding authors upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zhe-Cheng Wang, PhD, Department of Pharmacology, Dalian Medical University, No. 9 West Section, Shunnan Road, Shunkou District, Dalian 116044, Liaoning Province, China. wangzc03@dmu.edu.cn
Received: January 14, 2025
Revised: April 20, 2025
Accepted: May 26, 2025
Published online: June 14, 2025
Processing time: 150 Days and 0.2 Hours
Abstract
BACKGROUND

Hepatic ischemia-reperfusion (I/R) injury related to liver transplantation and hepatic resection remains a challenge in clinical practice. Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury. The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.

AIM

To clarify the protective mechanism of NIPSNAP1 against hepatic I/R, with a focus on mitophagy and mitochondrial dynamics, as well as the potential mechanism by which n6-methyladenosine (m6A) modification regulates NIPSNAP1.

METHODS

Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R. HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.

RESULTS

We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) expression in vivo and in vitro. NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics; in contrast, NIPSNAP1 overexpression resulted in the opposite effects. Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1, thereby regulating its mRNA stability.

CONCLUSION

NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis, serving as a novel target of the m6A reader IGF2BP2. Therefore, targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.

Keywords: Hepatic ischemia-reperfusion; 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1; Mitophagy; Mitochondrial dynamics; Interacted with insulin-like growing factor 2; mRNA-binding protein 2; mRNA stability

Core Tip: We confirmed the effect of 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) as a new target that controls mitophagy and mitochondrial dynamics in hepatic ischemia-reperfusion. Knockdown of NIPSNAP1 impaired mitophagy and disrupted mitochondrial dynamics, as evidenced by increased mitochondrial fission and reduced fusion. Further studies revealed that interacted with insulin-like growing factor 2 acts as an n6-methyladenosine reader to bind NIPSNAP1 mRNA and enhance its stability, thereby regulating NIPSNAP1 expression. These results suggest that the interacted with insulin-like growing factor 2/NIPSNAP1 axis may be a promising target for hepatic ischemia-reperfusion.