Chen Zixuan, Han Chengtao, Xie Huiwen, Chen Xingyu, Zhang Haojie, Sun Zongrun, Liu Min
Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Surgery, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biofactors. 2025 Mar-Apr;51(2):e70016. doi: 10.1002/biof.70016.
The development of resistance significantly reduces the efficacy of targeted therapies, such as sunitinib, in renal cell carcinoma (RCC) patients, emphasizing the need for novel therapeutic agents. Natural products, known for their diverse chemical structures and mechanisms of action, offer promising anti-tumor potential with favorable safety profiles and lower toxicity compared to synthetic drugs. 2-Undecanone, a natural compound extracted from Houttuynia cordata Thunb., has demonstrated anti-tumor effects, but its specific role in RCC treatment remains unclear. In this study, we integrated network pharmacology with in vitro experiments to explore the mechanisms underlying 2-Undecanone's effects on RCC. Our results reveal that 2-Undecanone effectively inhibits RCC cell viability, proliferation, and migration. Mechanistically, we discovered that 2-Undecanone induces ferroptosis in RCC cells by promoting reactive oxygen species (ROS) generation, intracellular Fe accumulation, glutathione (GSH) production, lipid peroxidation, and modulation of the STAT3/GPX4 signaling pathway. Furthermore, 2-Undecanone lowers the IC50 value of sunitinib in RCC cells, enhancing their sensitivity to this targeted therapy. Additionally, 2-Undecanone potentiates sunitinib-induced ferroptosis. In summary, our research reveals that 2-Undecanone enhances the sensitivity of RCC cells to sunitinib through targeting the STAT3/GPX4 pathway, providing new insights into potential therapeutic strategies for RCC.
耐药性的产生显著降低了靶向治疗药物（如舒尼替尼）对肾细胞癌（RCC）患者的疗效，这凸显了对新型治疗药物的需求。天然产物以其多样的化学结构和作用机制而闻名，与合成药物相比，具有良好的抗肿瘤潜力、安全性和较低的毒性。2-十一烷酮是从鱼腥草中提取的一种天然化合物，已显示出抗肿瘤作用，但其在RCC治疗中的具体作用仍不清楚。在本研究中，我们将网络药理学与体外实验相结合，以探索2-十一烷酮对RCC作用的潜在机制。我们的结果表明，2-十一烷酮能有效抑制RCC细胞的活力、增殖和迁移。机制上，我们发现2-十一烷酮通过促进活性氧（ROS）生成、细胞内铁积累、谷胱甘肽（GSH）产生、脂质过氧化以及调节STAT3/GPX4信号通路，诱导RCC细胞发生铁死亡。此外，2-十一烷酮降低了舒尼替尼在RCC细胞中的IC50值，增强了它们对这种靶向治疗的敏感性。此外，2-十一烷酮还增强了舒尼替尼诱导的铁死亡。总之，我们的研究表明，2-十一烷酮通过靶向STAT3/GPX4途径增强了RCC细胞对舒尼替尼的敏感性，为RCC潜在治疗策略提供了新的见解。
