Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Surg. Jun 27, 2025; 17(6): 106777
Published online Jun 27, 2025. doi: 10.4240/wjgs.v17.i6.106777
Mitochondrial alanyl-tRNA synthetase 2 mediates histone lactylation to promote ferroptosis in intestinal ischemia-reperfusion injury
Wei Dong, San-Xiong Huang, Mo-Liang Qin, Zhuo Pan
Wei Dong, Mo-Liang Qin, Zhuo Pan, Department of Hepatobiliary Pancreatic Surgery, Huzhou First People's Hospital, Huzhou 313000, Zhejiang Province, China
San-Xiong Huang, Department of Hepatobiliary Surgery, The First People’s Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China
Author contributions: Dong W, Huang SX, Qin ML, and Pan Z designed the research study; Dong W, Huang SX, Qin ML, and Pan Z performed the research.
Institutional animal care and use committee statement: Animal experiments were approved by the Research Ethics Committee of Huzhou First People's Hospital.
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: No additional data are available.
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: Zhuo Pan, Chief Physician, Department of Hepatobiliary Pancreatic Surgery, Huzhou First People's Hospital, No. 158 Back Plaza Road, Huzhou 532322, Zhejiang Province, China. m18267851073@163.com
Received: March 11, 2025
Revised: April 3, 2025
Accepted: May 12, 2025
Published online: June 27, 2025
Processing time: 80 Days and 20.8 Hours
Abstract
BACKGROUND

Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species. It has been extensively studied in various diseases, including cancer, Parkinson’s disease, and stroke. However, its precise role and underlying mechanisms in ischemia/ reperfusion injury, particularly in the intestinal ischemia-reperfusion (IIR), remain unclear. In current work, we aimed to investigate the participation of histone lactylation during IIR progression.

AIM

To investigate the role of mitochondrial alanyl-tRNA synthetase 2 (AARS2) in ferroptosis and its epigenetic regulation of acyl-CoA synthetase long-chain family member 4 (ACSL4) through histone lactylation during IIR injury.

METHODS

We established a mouse model to mimic IIR and conducted AARS2 knockdown as treatment. The expression of AARS2 in intestinal tissues was measured by western blot. The integrity of intestinal tissues was detected by hematoxylin and eosin staining, serum fatty acid-binding protein, protein levels of ZO-1 and occluding. An in vitro hypoxia-reperfusion (H/R) cell model was established, and cell viability was measured by CCK-8. The in vitro and in vivo ferroptosis was determined by the accumulation of Fe2+ and malondialdehyde (MDA). The epigenetic regulation of ACSL4 by AARS2 was detected by chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay.

RESULTS

We observed a notable elevated AARS2 level in intestinal tissue of mice in IIR model group, which was reversed by shAARS2 treatment. Knockdown of AARS2 repressed alleviated intestinal barrier disruption and repressed the accumulation of ferroptosis biomarker Fe2+ and MDA during IIR. The in vitro results showed that shAARS2 alleviated impaired cell viability caused by H/R, as well as repressed ferroptosis. Knockdown of AARS2 notably downregulated the RNA and protein expression of ACSL4. Mechanistically, knockdown of AARS2 downregulated the enrichment of H3K18 La modification on AARS2, as well as suppressed its promoter activity. Overexpression of AARS2 could abolish the protective effects of shACSL4 in vitro.

CONCLUSION

The elevation of AARS2 during IIR led to cell ferroptosis via epigenetically upregulating the expression of ACSL4. Our findings presented AARS2 as a promising therapeutic target for IIR.

Keywords: Intestinal ischemia-reperfusion injury; Ferroptosis; Histone lactylation; Mitochondrial alanyl-tRNA synthetase 2; Acyl-CoA synthetase long-chain family member 4; Epigenetic regulation; Lipid peroxidation; Intestinal barrier dysfunction; Reactive oxygen species; Cell death

Core Tip: This investigation reveals mitochondrial alanyl-tRNA synthetase 2 (AARS2) as a pivotal regulator of ferroptotic cell death in intestinal ischemia-reperfusion (I/R) injury. Our findings demonstrate that AARS2 augments histone H3K18 lactylation modification, which subsequently drives the transcriptional upregulation of acyl-CoA synthetase long-chain family member 4 through chromatin remodeling. This molecular cascade potentiates the accumulation of lipid peroxidation products and exacerbates intestinal epithelial damage. Pharmacological inhibition of AARS2 effectively suppresses ferroptosis progression and maintains mucosal barrier integrity, establishing its clinical relevance for managing I/R-associated tissue injury.