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

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.

Automated summary

Lipid peroxidation-induced ferroptosis is a newly recognized type of programmed cell death. In this study, it was found that irradiation increased the expression of ferroptosis promotive genes and decreased the expression of ferroptosis suppressive genes in murine intestine tissues. Further experiments showed that ACSL4 is an important component for ferroptosis execution and its expression was upregulated in irradiated intestine tissues. Additionally, the ACSL4 inhibitor troglitazone was able to suppress lipid peroxidation and protect against tissue damage after irradiation.