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ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis - PubMed

  • ️Sat Jan 01 2022

ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis

Qian Ji et al. Cell Death Discov. 2022.

Abstract

Lipid peroxidation-induced ferroptosis is a newly recognized type of programmed cell death. With the method of RNA sequencing, we found that irradiation (IR) markedly increased the expression of ferroptosis promotive genes, whereas reduced the expression of ferroptosis suppressive genes in murine intestine tissues, when compared with those of liver and lung tissues. By using ferroptosis inducer RSL-3 and inhibitor liproxstatin-1, we found that ferroptosis is essential for IR-induced intestinal injury. Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) is an important component for ferroptosis execution, and we found that ACSL4 expression was significantly upregulated in irradiated intestine tissues, but not in liver or lung tissues. Antibacterial and antifungal regents reduced the expression of ASCL4 and protected against tissue injury in irradiated intestine tissues. Further studies showed that troglitazone, a ACSL4 inhibitor, succeeded to suppresses intestine lipid peroxidation and tissue damage after IR.

© 2022. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The effect of IR on transcriptome of liver, lung, and intestine of mice.

A Representative images of the hematoxylin and eosin (H&E) staining of the liver, lung, and intestine from control and irradiated (IR) mice. The scale bar is 50 μm. B Changes of RNA transcription profiles in the liver, lung, and intestine tissues of the mice in the control group and IR group. Green bars represent down-regulation of gene expression and red bars represent up-regulation of gene expression. C KEGG Biological Process analyses differentially expressed genes in the liver, lung, and intestine of mice.

Fig. 2
Fig. 2. Irradiation induces ferroptosis in intestinal tissue.

A Heatmap of ferroptosis promoters and inhibitors in liver, lung, and intestine tissues of mice after IR. B Reverse transcription polymerase chain reaction of ferroptosis-related genes in liver, lung, and intestine of mice. C Analysis of GSH/GSSG and MDA in liver, lung, and intestine after IR of mice. P values are derived from the permutation test, two-sided Student’s t test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Fig. 3
Fig. 3. Ferroptosis promotes radiation injury in mice.

A Histological scores of intestinal tissues of mice after IR. Ki67+ cells were counted in seven crypts. Representative images of the H&E staining and Ki67 staining of the intestine from control, vehicle, RSL-3, Liproxstatin-1, and RSL-3+Liproxstatin-1 groups. B Analysis of GSH/GSSG and MDA in intestinal control, vehicle, RSL-3, Liproxstatin-1, and RSL-3+Liproxstatin-1 of mice. C Analysis of intestinal permeability of mice in control, vehicle, RSL-3, liproxstatin-1, and RSL-3+Liproxstatin-1 treatment groups to FITC-Dextran. P values are derived from permutation test, two-sided Student’s t test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Fig. 4
Fig. 4. Intestinal bacteria and fungi promote radiation intestinal injury and ferroptosis.

A Analysis of the expression levels of ferroptosis-related genes GPX4 and ACSL4 in intestinal tissues of mice in control, vehicle, antibacterial and antifungal. B Histological scores of intestinal tissues of mice after IR. Ki67+ cells were counted in seven crypts. Representative images of the H&E staining and Ki67 staining of the intestine from control, vehicle, antibacterial and antifungal. C Analysis of GSH/GSSG and MDA in intestinal control, vehicle, antibacterial, and antifungal of mice. P values are derived from permutation test, two-sided Student’s t test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Fig. 5
Fig. 5. Intestinal bacteria and fungi promote ferroptosis by inducing ACSL4 expression.

A Histological scores of intestinal tissues of mice after IR. Ki67+ cells were counted in seven crypts. Representative images of the H&E staining and Ki67 staining of the intestine from control, vehicle, and troglitazone. B Analysis of GSH/GSSG and MDA in intestinal control, vehicle, and troglitazone of mice. P values are derived from permutation test, two-sided Student’s t test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

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