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

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.