Renal cell carcinoma (RCC) continues to pose a significant clinical challenge due to its high resistance to conventional therapies. Sunitinib, a first-line treatment for metastatic RCC, is often limited by acquired resistance, necessitating novel therapeutic strategies. Chrysin, a natural flavonoid with known anticancer properties, has shown potential in various malignancies; however, its role in RCC is still not well understood. This research employed network pharmacology and molecular docking techniques to identify the primary targets of Chrysin in RCC, identifying EGFR as the central target. Functional experiments demonstrated that Chrysin significantly reduced the proliferation and migration of RCC cells. Further investigation revealed that Chrysin induced ferroptosis, as evidenced by increased ROS levels, Fe2+ accumulation, GSH depletion, and lipid peroxidation.d Through its mechanisms, Chrysin suppressed the PI3K/Akt signaling pathway, which resulted in the reduced expression of SLC7A11 and GPX4. Rescue experiments confirmed that activation of PI3K/Akt reversed Chrysin-induced ferroptosis. Additionally, Chrysin enhanced the sensitivity of RCC cells to sunitinib by potentiating ferroptosis. These findings demonstrate that chrysin enhances sunitinib sensitivity in RCC by targeting the PI3K/Akt/GPX4 axis to induce ferroptosis, providing a novel strategy for RCC treatment.Copyright © 2025. Published by Elsevier Inc.