Curculigoside Induces Ferroptosis in Non‐Small Cell Lung Cancer Cells Through a Mechanism Involving Wilms' Tumor 1‐Associating Protein‐Mediated m6A Modification of GTP Cyclohydrolase 1

Ferroptosis plays a critical role in non-small cell lung cancer (NSCLC) progression. Curculigoside (Cur) exhibits anti-cancer properties. This study aimed to elucidate the precise action of Cur on NSCLC ferroptosis. Various concentrations of Cur were used to treat A549 and H520 cells to evaluate its cytotoxicity. The regulation of Wilms' tumor 1-associating protein (WTAP) on GTP cyclohydrolase 1 (GCH1) was verified by methylated RNA immunoprecipitation (MeRIP) and mRNA stability assays. Cur suppressed proliferative, migratory, and invasive capacities of A549 and H520 cells in vitro and reduced tumor growth in A549-derived subcutaneous xenografts in vivo. Cur induced ferroptosis in A549 and H520 cells. Mechanistically, Cur decreased the protein levels of GCH1 and WTAP, and WTAP mediated the N6-methyladenosine (m6A) methylation and stabilization of GCH1 mRNA. GCH1 depletion promoted NSCLC cell ferroptosis and impeded their malignant phenotypes. Moreover, overexpression of GCH1 reversed Cur-induced ferroptosis and malignant phenotype inhibition in A549 and H520 NSCLC cells. Our study suggested that Cur induced ferroptosis and suppressed malignant phenotypes in NSCLC in part through the WTAP-GCH1 axis, thereby revealing a novel mechanism for its therapeutic potential.