4′‐Hydroxychalcone Induces Ferroptosis in Glioblastoma Through the xCT/GSH/GPX4 Axis Under the Regulation of the AKT/mTORC1/4EBP1 Pathway

ABSTRACT Glioblastoma multiforme (GBM) is a common and malignant tumor in the field of neurosurgery. Natural chemotherapeutic agents are an appealing option due to their diverse activities and low cost. Ferroptosis, a form of programmed cell death, holds great potential for treating resistant cancers. The specific mechanism by which 4′‐hydroxychalcone extracted from Glycyrrhiza glabra L. induces glioma cell death remains unclear. This study aims to explore the molecular mechanism of 4′‐hydroxychalcone's effect on glioma cells. Through CCK‐8 assay, cell scratch and invasion assay, q‐PCR technology, WB detection and immunofluorescence, the inhibitory effect of 4′‐hydroxychalcone on glioma and its mechanism were analyzed. The study found that 20 μM 4′‐hydroxychalcone could induce ferroptosis and inhibit the proliferation and epithelial‐mesenchymal transition of glioma cells. Subsequent analysis revealed that this process of ferroptosis was triggered through the xCT/GSH/GPX4 axis, which was regulated by the AKT/mTORC1/4EBP1 pathway. Similar tumor inhibitory effects to the clinical drug temozolomide were also observed in the in vivo tumor model. Long‐term animal toxicity experiments showed that high doses of 4′‐hydroxychalcone (100 mg/kg) did not cause damage to the organs of the animals. This study provides new insights into tumor ferroptosis research and traditional Chinese medicine‐based treatment of GBM.