PPARγ is a potential therapeutic target for radiation enteritis via suppressing ferroptosis, mediated by the GAPDH/glycosylation axis

Abstract Background and Purpose Radiation enteritis (RE) is a severe complication after radiotherapy with no specific therapeutic agents. Here, we have attempted to identify the key therapeutic targets for RE, to advance drug development. Experimental Approach Therapeutic targets were screened and identified using RE patients' intestinal samples, bioinformatics, and mouse models. RNA sequencing, electron microscopy, metabolomics, glycolytic flux, co‐immunoprecipitation, molecular docking, point mutation were used to identify mechanisms. Key Results Analysis of gene changes in response to ionising radiation showed extensive regulation of several differentially expressed genes by PPARγ, as well as its deficiency in activation and expression in RE. Both activation and overexpression of PPARγ significantly antagonised RE in vivo. Mechanistically, PPARγ specifically limited ferroptosis in intestinal epithelial cells exposed to ionising radiation, and its selective activation was more effective than full activation because of the reduced effect on the ferroptosis‐driving genes PTEN and SAT1 . Furthermore, ionising radiation caused the greatest changes in glucose metabolism. PPARγ targeted GAPDH at Lys107 to shift glycolysis to the hexosamine biosynthesis pathway, thereby enhancing glycosylation. In ionising radiation‐induced ferroptosis, O/N ‐GlcNAcylation initially played antagonistic roles and later mediated the process, and they assisted PPARγ in restraining lysosomal degradation of heavy‐chain ferritin (FTH1) and the transferrin receptor TFRC, thus controlling storage and transport of iron, and consequently alleviated ferroptosis. Conclusion and Implications PPARγ is a potential therapeutic target for RE, as it elicits GAPDH‐mediated glucose metabolic reprogramming and alleviates ionising radiation‐induced ferroptosis, in a glycosylation‐dependent manner.