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Updated: May 2, 2026
Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT
Published on: January 22, 2018
PPARγ is a potential therapeutic target for radiation enteritis via suppressing ferroptosis, mediated by the
Xi Zeng1, Liefeng Zhang2, Hong Lu3
1Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
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.
Insights
Peroxisome proliferator-activated receptor gamma (PPARγ) activation targets glucose metabolism to limit ferroptosis, offering a novel therapeutic strategy for radiation enteritis (RE). This discovery advances drug development for RE complications.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Radiation enteritis (RE) is a severe radiotherapy complication lacking specific treatments.
- Identifying novel therapeutic targets is crucial for advancing drug development for RE.
Purpose of the Study:
- To identify key therapeutic targets for radiation enteritis (RE).
- To investigate the role of PPARγ in RE pathogenesis and explore its therapeutic potential.
Main Methods:
- Utilized RE patient samples, bioinformatics, and mouse models for target screening.
- Employed RNA sequencing, metabolomics, and molecular assays to elucidate mechanisms.
- Investigated the role of PPARγ in ferroptosis and glucose metabolism.
Main Results:
- PPARγ activation significantly antagonized RE in vivo, with deficiency observed in RE patients.
- PPARγ limited ionising radiation-induced ferroptosis in intestinal epithelial cells.
- PPARγ reprogrammed glucose metabolism via GAPDH, enhancing glycosylation and ferroptosis alleviation.
Conclusions:
- PPARγ is a promising therapeutic target for RE.
- PPARγ's mechanism involves GAPDH-mediated metabolic reprogramming and glycosylation-dependent ferroptosis inhibition.
- Targeting PPARγ offers a novel strategy for managing radiation enteritis.
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