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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Lysine acetyltransferase 2A-mediated succinylation of adenosine monophosphate-activated protein kinase suppresses gallstone formation by inhibiting inflammation and pyroptosis
Xin-Xing Wang, Ming-Ze Ma, Li-Chao Zhu, Long-Fei Dai, Chuan Qin, Shuai Shao, Xian-Wen Xu, Ru-Xin Gao, Zhen-Hai Zhang
Xin-Xing Wang, Long-Fei Dai, Shuai Shao, Xian-Wen Xu, Ru-Xin Gao, Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
Ming-Ze Ma, Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
Li-Chao Zhu, Department of Pediatric Surgery, Shandong Provincial Hospital, Jinan 250021, Shandong Province, China
Chuan Qin, Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Jinan 250021, Shandong Province, China
Zhen-Hai Zhang, Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong Province, China
Co-first authors: Xin-Xing Wang and Ming-Ze Ma.
Author contributions: All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript; Wang XX and Ma MZ drafted the work and revised it critically for important intellectual content; Zhu LC, Dai LF, Qin C, Shao S, Xu XW and Gao RX were responsible for the acquisition, analysis and interpretation of data for the work; Wang XX, Ma MZ and Zhang ZH made substantial contributions to the conception or design of the work; All authors read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82000579 and No. 81870205; and Natural Science Foundation of Shandong Province, No. ZR2021QH061 and No. ZR2021QH186.
Institutional animal care and use committee statement: The animal study was approved by the Experimental Animal Welfare Ethics Committee of MDKN Biotechnology Co., Lt (Approval No. MDKN-2024-129). All methods were carried out in accordance with relevant guidelines and regulations.
Conflict-of-interest statement: The authors declare that they have no competing interests.
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 used and/or analysed during the current study are available from the corresponding author on 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: Zhen-Hai Zhang, Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, No. 324 Jingwu Road, Huaiyin District, Jinan 250021, Shandong Province, China.
drzhangzhenhai@163.com
Received: May 30, 2025
Revised: July 11, 2025
Accepted: September 15, 2025
Published online: October 21, 2025
Processing time: 145 Days and 7.2 Hours
BACKGROUND
Cholelithiasis is a prevalent biliary tract disorder primarily characterized by gallbladder or biliary stone formation. Although succinylation has been extensively studied as a protein post-translational modification, its role in cholelithiasis remains unexplored.
AIM
To investigate the functional role of succinylation in cholelithiasis and determine its underlying molecular mechanisms.
METHODS
A murine cholelithiasis model was established through high-fat diet feeding, followed by isolation of mouse gallbladder mucosal epithelial cells (GMECs) for in vitro analysis. Gallbladder tissues and serum samples were collected for subsequent analysis. Inflammatory cytokine production was quantified using enzyme-linked immunosorbent assay. Pyroptosis was analyzed by flow cytometry, while succinylation- and pyroptosis-related protein expression was detected via western blot.
RESULTS
Our findings demonstrated that lysine acetyltransferase 2A (KAT2A)-mediated succinylation regulated gallstone formation. KAT2A overexpression inhibited the pyroptosis, inflammatory responses, and promoted the activation of the adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) signaling pathway in GMECs. Mechanistically, AMPK exhibited succinylation at lysine 170 (K170). Notably, AMPK inhibition significantly increased pyroptosis rates, inflammatory responses, and pyroptosis-related protein expression in GMECs. Furthermore, in vivo experiments revealed that KAT2A overexpression suppressed both inflammation and gallstone formation.
CONCLUSION
KAT2A-mediated succinylation of AMPK inhibited cholelithiasis progression by modulating the AMPK/SIRT1 signaling pathway, offering potential therapeutic strategies for this condition.
Core Tip: Cholelithiasis is a common biliary disorder with complex mechanisms. Lysine succinylation, a protein post-translational modification, remains unstudied in this condition. This study reveals that lysine acetyltransferase 2A-mediated succinylation of adenosine monophosphate-activated protein kinase (AMPK) inhibits cholelithiasis by regulating inflammation via the AMPK/sirtuin 1 pathway. This study provides a groundbreaking perspective on cholelithiasis mechanisms and position succinylation as a potential therapeutic target, addressing a significant gap in the field.
