Ursolic acid enhances radiosensitivity in esophageal squamous cell carcinoma by modulating p53/SLC7A11/GPX4 pathway-mediated ferroptosis.

Background: Radiotherapy is essential for the management of esophageal squamous cell carcinoma (ESCC). However, ESCC cells are highly susceptible to developing resistance to radiotherapy, leading to poor prognosis. Ursolic acid (UA) is a herbal monomer, has multiple medicinal benefits like anti-tumor. The impact of UA on the sensitivity of ESCC cells to radiotherapy is currently unclear.

Methods: The impact of UA and ionizing radiation (IR) on the viability of TE-1 and KYSE30 cells was assessed by the MTT assay. EdU staining, flow cytometry, clone formation, Wound healing and Transwell assay detected the biological properties of ESCC cells. FerroOrange, DCFH-DA, and kits to detect the influences of UA and/or IR treatment on cellular ferroptosis. The levels of p53/solute carrier family 7a member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway proteins were detected by Western blot. Additionally, a subcutaneous graft tumor model was constructed in nude mice.

Results: 10 μM UA reduced the viability and induced death of ESCC cells. UA enhanced the impacts of IR by suppressing cell proliferation, migration and invasion, inducing cell death, and causing cell cycle arrest. Ferroptosis inhibitor impaired the inhibitory impacts of UA and IR on the biological properties of ESCC cells. The combination of UA and IR led to ferroptosis through the modulation of the p53/SLC7A11/GPX4 pathway, and UA enhanced the responsiveness of ESCC cells to IR both in vitro and in vivo.

Conclusion: UA inhibits the malignant biological behavior of ESCC by modulating ferroptosis through the p53/SLC7A11/GPX4 pathway, and enhances the sensitivity of ESCC cells to IR.