Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated antioxidant capacity. However, its mechanistic integration with radiotherapy remains incompletely understood. Methods: We compared the effects of three clinically approved VEGFR-targeting tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib, and ripretinib, on NSCLC cell viability with and without radiation. Subsequent mechanistic studies focused on cabozantinib and included ferroptosis rescue assays (ferrostatin-1, deferoxamine), lipid ROS quantification, glutathione assays, clonogenic survival, co-immunoprecipitation of BECN1–SLC7A11 complexes, and BECN1 knockdown by siRNA and shRNA. Results: All three TKIs were evaluated for cytotoxicity, but only cabozantinib significantly reduced NSCLC cell viability in combination with radiation in a ferroptosis-dependent manner. Cabozantinib inhibited STAT3 phosphorylation and downregulated MCL1, resulting in the release of BECN1. This allowed BECN1 to bind and suppress SLC7A11, disrupting system Xc−function, depleting glutathione, and promoting lipid ROS accumulation. Genetic silencing of BECN1 reversed these effects and restored redox balance and clonogenic capacity. Lenvatinib and ripretinib failed to elicit similar responses, indicating that the inhibition of non-VEGFR targets (e.g., MET, AXL) may be essential for ferroptosis induction by cabozantinib. Conclusions: Cabozantinib enhances the radiosensitization of NSCLC cells through ferroptosis induction mediated by the suppression of the STAT3/MCL1/BECN1/SLC7A11 axis. These findings uncover a novel mechanism linking kinase inhibition to redox imbalance and suggest that the pharmacologic modulation of ferroptosis using multi-target TKIs may represent a rational approach to overcome radioresistance in NSCLC.
**背景/目的：** 非小细胞肺癌（NSCLC）的固有放射抵抗部分由适应性氧化还原机制驱动，该机制可防止氧化性细胞死亡。铁死亡是一种以脂质过氧化为特征的铁依赖性调节性细胞死亡形式，已成为抗氧化能力升高的肿瘤中潜在的治疗弱点。然而，其与放射治疗的机制整合仍不完全清楚。 **方法：** 我们比较了三种临床获批的靶向VEGFR的酪氨酸激酶抑制剂（TKI）——卡博替尼、仑伐替尼和瑞普替尼，在有无放射线照射下对NSCLC细胞活力的影响。随后的机制研究聚焦于卡博替尼，包括铁死亡挽救实验（ferrostatin-1、去铁胺）、脂质ROS定量、谷胱甘肽测定、克隆形成存活、BECN1–SLC7A11复合物的免疫共沉淀，以及通过siRNA和shRNA敲低BECN1。 **结果：** 评估了三种TKI的细胞毒性，但只有卡博替尼以铁死亡依赖的方式，与放射线联合使用时显著降低了NSCLC细胞活力。卡博替尼抑制STAT3磷酸化并下调MCL1，导致BECN1释放。这使得BECN1能够结合并抑制SLC7A11，破坏系统Xc−功能，耗竭谷胱甘肽，并促进脂质ROS积累。BECN1的基因沉默逆转了这些效应，恢复了氧化还原平衡和克隆形成能力。仑伐替尼和瑞普替尼未能引发类似反应，表明对非VEGFR靶点（如MET、AXL）的抑制可能对卡博替尼诱导铁死亡至关重要。 **结论：** 卡博替尼通过抑制STAT3/MCL1/BECN1/SLC7A11轴介导的铁死亡诱导，增强了NSCLC细胞的放射增敏作用。这些发现揭示了一种将激酶抑制与氧化还原失衡联系起来的新机制，并提示使用多靶点TKI对铁死亡进行药理学调控，可能是克服NSCLC放射抵抗的合理策略。
肿瘤(癌症)患者之家