Published online Jun 27, 2025. doi: 10.4240/wjgs.v17.i6.106777
Revised: April 3, 2025
Accepted: May 12, 2025
Published online: June 27, 2025
Processing time: 80 Days and 20.8 Hours
Ferroptosis is a newly recognized form of regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species. It has been ex
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.
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 epi
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.
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.
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.