铁死亡（Ferroptosis）是一种依赖氧气和铁催化剂的途径，由于其可管理的调节、直接控制和免疫原性，具有作为抗癌治疗的潜力。癌细胞对铁死亡诱导的敏感性因其代谢、遗传和信号通路的差异而异，促使采用联合治疗。本研究中，我们对MDA-MB-231、A549和HeLa细胞进行了药物联合筛选，包括索拉非尼（SOR）与辛伐他汀（SIM）、苯乙基异硫氰酸酯和三角碱的联合应用，以评估其细胞毒性。SOR-SIM联合在MDA-MB-231、A549和HeLa细胞中表现出协同作用，计算的组合指数（CI）值分别为0.66、0.53和0.59。此外，与铁脱氧谷胱甘肽-1（ferrostatin-1）联合处理导致IC50值浓度依赖性增加。此外，SOR+SIM在所有三个细胞系中均显著降低了谷胱甘肽（GSH）水平，增加了丙二醛（MDA）水平，并引起线粒体膜去极化，表明它们具有诱导铁死亡的潜力。体内研究显示与对照组、SIM组和SOR组相比，瘤体体积显著减小了3.53倍、2.55倍和1.47倍。毒性评估显示除了SOR+SIM联合使用引起的红细胞萎缩和膜扭曲效应外，体内器官的生物标志物水平无显著变化，没有观察到可见形变。综上所述，我们的研究结果强调SOR+SIM联合方案作为一种对癌症治疗的有效策略的潜力，并强调进一步研究靶向药物传递系统以确保其安全性的重要性。© 2023年作者，American Association of Pharmaceutical Scientists独家许可。

Ferroptosis, a pathway dependent on oxygen and iron catalysts, holds promise as a therapeutic approach for cancer treatment due to its manageable regulation, direct control, and immunogenic properties. The sensitivity of cancer cells to ferroptosis induction varies based on their metabolic, genetic, and signalling pathways, prompting the use of combination therapy. In this study, we conducted a screening of drug combinations, including sorafenib (SOR) with simvastatin (SIM), phenethyl isothiocyanate, and trigonelline, in MDA-MB-231, A549, and HeLa cells to assess their cytotoxicity. The SOR-SIM combination exhibited a synergistic effect in MDA-MB-231, A549, and HeLa cells, with calculated CI values of ~ 0.66, 0.53, and 0.59, respectively. Furthermore, co-treatment with ferrostatin-1 resulted in a concentration-dependent increase in the IC50 values. Additionally, SOR + SIM demonstrated a significant reduction in GSH levels, an increase in MDA levels, and mitochondrial membrane depolarization across all three cell lines, indicating their ferroptosis inducing potential. In-vivo studies showed a significant reduction in tumor volume by 3.53-, 2.55-, and 1.47-fold compared to control, SIM, and SOR, respectively. Toxicity assessments revealed insignificant changes in biomarker levels and no observable deformations in isolated organs, except for erythrocyte shrinkage and membrane scrambling effects caused by the SOR + SIM combination. Overall, our findings highlight the potential of the SOR + SIM combination as an effective strategy for cancer treatment, emphasizing the importance of further research in targeted drug delivery systems to ensure its safety.© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.