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Updated: Sep 30, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
Ferroptosis regulates metabolic inflammation-driven tumorigenesis in obesity-related gastric cancer
Mizuki Tanabe1, Kaname Uno2, Toru Tamahara3
1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Background And Aims:
The incidence of gastric cardia adenocarcinoma (GCA) has increased with increasing prevalence of metabolic syndrome (MetS). Peroxisome proliferator-activated receptor-delta (PPAR-δ) emerged as a key target in MetS and carcinogenesis. We aimed to elucidate its role in GCA progression.
Methods:
Male K19-Wnt1/C2mE mice were fed a control or high-fat diet (HFD) with or without the PPAR-δ agonist GW-501516 or the PPAR-δ antagonist GSK-3787 (GSK). The involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) in the PPAR-δ-regulated, metabolism-driven tumorigenesis was examined by comparing wild-type and Nrf2-deficient conditions.
Results:
In HFD+GSK-treated K19-Wnt1/C2mE mice with metabolic endotoxemia, granular-nodular tumors at the squamocolumnar junction (SCJ) were greater than those in the other groups. Intratumor expression of the NAD(P)H quinone dehydrogenase 1 (NQO1) and glutathione peroxidase 4 (GPx4) proteins increased and the plasma levels of dysbiosis-related metabolites for tumor energy metabolism increased. In HFD+GSK-treated Nrf2-deficient mice, tumors shrank with decreases in NQO1 and GPx4 proteins expression and increases in the malondialdehyde level and GSSG/GSH ratio, and the plasma levels of metabolites for energy metabolism and ferroptosis resistance decreased. Suppression of PPAR-δ signaling in AGS cells treated with GSK or a small interfering RNA (siRNA) inhibited ferroptosis by increasing solute carrier family 7 member 11 (SLC7A11) expression and activating NRF2 signaling. Transfection with NRF2 siRNA decreased the GSK-induced upregulation of SLC7A11, and NRF2 directly regulates SLC7A11 transcription by binding to its promoter.
Conclusions:
Cotreatment with HFD and GSK may promote SCJ tumor progression by suppressing ferroptosis through intratumoral NRF2 signaling and dysbiosis-related metabolites, indicating a negative role of PPAR-δ signaling on MetS-related SCJ tumorigenesis.
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