Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2024; 30(12): 1764-1776
Published online Mar 28, 2024. doi: 10.3748/wjg.v30.i12.1764
ALKBH5 suppresses autophagic flux via N6-methyladenosine demethylation of ZKSCAN3 mRNA in acute pancreatitis
Tao Zhang, Shuai Zhu, Geng-Wen Huang
Tao Zhang, Shuai Zhu, Geng-Wen Huang, Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China.
Tao Zhang, Shuai Zhu, Geng-Wen Huang, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China.
Co-corresponding authors: Shuai Zhu and Geng-Wen Huang.
Author contributions: Zhu S and Huang GW conceived, designed and refined the study protocol; Zhang T finished the experiments, collected and analyzed the data and drafted the manuscript; Zhu S and Huang GW reviewed and revised the manuscript. All authors had access to the study data and reviewed and approved the final manuscript. Zhu S and Huang GW contributed equally to this work as co-corresponding authors. The reasons for designating Zhu S and Huang GW as co-corresponding authors are twofold. First, co-corresponding authors jointly conceived the overall design of the study and revised the manuscript. Second, they jointly provided financial support for the study. In summary, we believe that designating Zhu S and Huang GW as co-corresponding authors accurately reflects our team's collaborative spirit, equal contributions, and diversity.
Supported by National Natural Science Foundation of China, No. 81802450; and Natural Science Foundation of Hunan Province, No. 2020JJ4133 and No. 2021JJ31135.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Xiangya Hospital of Central South University.
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 Xiangya Hospital of Central South University.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Shuai Zhu, MD, PhD, Surgeon, Department of Pancreatic Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha 410005, Hunan Province, China. zhushuai@csu.edu.cn
Received: November 11, 2023
Peer-review started: November 11, 2023
First decision: January 24, 2024
Revised: February 3, 2024
Accepted: March 6, 2024
Article in press: March 6, 2024
Published online: March 28, 2024
Processing time: 138 Days and 6.2 Hours
ARTICLE HIGHLIGHTS
Research background

The incidence of acute pancreatitis (AP) is increasing annually, and its mortality rate is high. Impaired autophagy is a key factor in the occurrence and development of AP. Therefore, it is crucial to clarify the regulatory mechanism of autophagy in AP.

Research motivation

Evidence has shown that ALKBH5 and ZKSCAN3 can regulate autophagy in a variety of diseases, but there are no relevant studies on AP.

Research objectives

We aimed to explore the regulatory functions and mechanisms of autophagy mediated by ALKBH5 and ZKSCAN3 in AP.

Research methods

The AP mouse cell line was constructed with cerulein, and the levels of inflammatory factors were detected via ELISA. Similarly, the expression of ALKBH5, ZKSCAN3 and autophagy-related proteins was detected via qPCR, western blot, and immunofluorescence. Microscopic manifestations of autophagy in the cell model were observed via transmission electron microscopy. Additionally, RNA binding protein immunoprecipitation was used to analyze the interaction between ALKBH5 and ZKSCAN3.

Research results

The expression of ALKBH5 and ZKSCAN3 was upregulated in the AP model, and the trend toward increased expression of autophagy-related genes suggested that autophagic flux was blocked in AP. Autophagy was improved by inhibiting the expression of ALKBH5 and ZKSCAN3. ZKSCAN3 mRNA has m6A binding sites, and ALKBH5 can upregulate its expression by demethylating ZKSCAN3, which inhibits autophagic flux, thereby aggravating inflammation in AP.

Research conclusions

ALKBH5 suppresses autophagic flux by demethylating the m6A site on ZKSCAN3 mRNA, consequently promoting the onset and progression of AP.

Research perspectives

We proved that ALKBH5 inhibits autophagy by upregulating ZKSCAN3, thereby promoting the occurrence and development of AP and providing new ideas for future research on autophagy regulation and early drug intervention in AP.