Chen Zixuan, Li Weiyuan, Jia Boshen, Yin Guohuan, Sun Zongrun, Tong Yanjun, Cheng Sheng, Liu Min
Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
Center for Rare Diseases, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
Toxicol Appl Pharmacol. 2025 Nov;504:117531. doi: 10.1016/j.taap.2025.117531. Epub 2025 Aug 21.
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, Fe 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.
肾细胞癌（RCC）由于对传统疗法具有高度抗性，仍然构成重大的临床挑战。舒尼替尼是转移性RCC的一线治疗药物，但常受到获得性耐药的限制，因此需要新的治疗策略。白杨素是一种具有已知抗癌特性的天然黄酮类化合物，已在多种恶性肿瘤中显示出潜力；然而，其在RCC中的作用仍未得到充分了解。本研究采用网络药理学和分子对接技术来确定白杨素在RCC中的主要靶点，确定表皮生长因子受体（EGFR）为核心靶点。功能实验表明，白杨素显著降低了RCC细胞的增殖和迁移。进一步研究表明，白杨素诱导了铁死亡，表现为活性氧水平升高、铁积累、谷胱甘肽消耗和脂质过氧化。通过其作用机制，白杨素抑制了PI3K/Akt信号通路，导致溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达降低。挽救实验证实，PI3K/Akt的激活逆转了白杨素诱导的铁死亡。此外，白杨素通过增强铁死亡增强了RCC细胞对舒尼替尼的敏感性。这些发现表明，白杨素通过靶向PI3K/Akt/GPX4轴诱导铁死亡来增强RCC对舒尼替尼的敏感性，为RCC治疗提供了一种新策略。
