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

doi:10.4240/wjgs.v17.i6.106777

Mitochondrial alanyl-tRNA synthetase 2 mediates histone lactylation to promote ferroptosis in intestinal ischemia-reperfusion injury

World J Gastrointest Surg. 2025 Jun 27;17(6):106777. doi: 10.4240/wjgs.v17.i6.106777.

Authors

Wei Dong¹, San-Xiong Huang², Mo-Liang Qin¹, Zhuo Pan³

Affiliations

¹ Department of Hepatobiliary Pancreatic Surgery, Huzhou First People's Hospital, Huzhou 313000, Zhejiang Province, China.
² Department of Hepatobiliary Surgery, The First People's Hospital of Huzhou, Huzhou 313000, Zhejiang Province, China.
³ Department of Hepatobiliary Pancreatic Surgery, Huzhou First People's Hospital, Huzhou 313000, Zhejiang Province, China. m18267851073@163.com.

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