非凋亡性程序细胞死亡诱导剂作为抗癌药物的开发已经成为一个癌症治疗领域。铁死亡是一种由氧化还原失衡和功能异常的活性氧清除引发的铁离子驱动的程序细胞死亡，该细胞死亡过程在索拉非尼布和PD-1/PD-L1免疫疗法期间被触发。DFIQ是一种喹啉衍生物，通过破坏自噬流量和促进活性氧积累来促进凋亡。我们的初步实验表明，DFIQ参与了铁死亡敏感化过程。因此，在本研究中，我们的目标是揭示DFIQ在铁死亡敏感化过程中的作用机制，并评估DFIQ的临床潜力。我们在非小细胞肺癌细胞系H1299、A549和H460中使用铁死亡诱导剂(DFIQ)进行了处理，并在不同时间点分析了细胞存活率、蛋白质表达、活性氧生成和荧光染色。使用ImageJ进行共定位分析。DFIQ使细胞对erastin和RSL3等铁死亡诱导剂敏感，IC50至少降低了0.5倍。通过测量活性氧积累来探索DFIQ的作用机制，结果表明DFIQ和铁死亡诱导剂处理促进了活性氧积累和SOD1/SOD2切换。线粒体是已知活性氧的来源，DFIQ/铁死亡诱导剂治疗时产生了高水平的活性氧。RSL3处理促进了线粒体损伤和线粒体自噬，一种与自噬相关的线粒体再生系统，DFIQ联合处理导致线粒体蛋白的积累，表明了线粒体自噬通量的破坏。因此，在与DFIQ联合处理的细胞中测量自噬通量。发现DFIQ处理破坏了自噬通量，导致受损线粒体的积累，最终引发铁死亡。此外，评估了DFIQ对索拉非尼布等临床铁死亡诱导剂效应的影响，发现DFIQ可使非小细胞肺癌细胞对索拉非尼布敏感，并促进铁死亡。该研究表明，DFIQ不仅促进非小细胞肺癌的凋亡，而且通过破坏自噬通量使细胞对铁死亡敏感，导致功能受损的线粒体积累，从而产生铁死亡。铁死亡是癌症治疗中的一个新的治疗靶点。DFIQ在非小细胞肺癌中显示出增强铁死亡诱导剂的效果的潜力，并可作为铁死亡介导治疗的潜在辅助治疗剂。© 2023. BioMed Central Ltd., part of Springer Nature.

The development of nonapoptotic programmed cell death inducers as anticancer agents has emerged as a cancer therapy field. Ferroptosis, ferrous ion-driven programmed cell death that is induced by redox imbalance and dysfunctional reactive oxygen species (ROS) clearance, is triggered during sorafenib and PD-1/PD-L1 immunotherapy. DFIQ, a quinoline derivative, promotes apoptosis by disrupting autophagic flux and promoting ROS accumulation. Our pilot experiments suggest that DFIQ participates in ferroptosis sensitization. Thus, in this study, we aimed to reveal the mechanisms of DFIQ in ferroptosis sensitization and evaluate the clinical potential of DFIQ.We treated the non-small cell lung cancer (NSCLC) cell lines H1299, A549, and H460 with the ferroptosis inducer (FI) DFIQ and analyzed viability, protein expression, ROS generation, and fluorescence staining at different time points. Colocalization analysis was performed with ImageJ.DFIQ sensitized cells to FIs such as erastin and RSL3, resulting in a decrease in IC50 of at least 0.5-fold. Measurement of ROS accumulation to explore the underlying mechanism indicated that DFIQ and FIs treatment promoted ROS accumulation and SOD1/SOD2 switching. Mitochondria, known ROS sources, produced high ROS levels during DFIQ/FI treatment. RSL3 treatment promoted mitochondrial damage and mitophagy, an autophagy-associated mitochondrial recycling system, and cotreatment with DFIQ induced accumulation of mitochondrial proteins, which indicated disruption of mitophagic flux. Thus, autophagic flux was measured in cells cotreated with DFIQ. DFIQ treatment was found to disrupt autophagic flux, leading to accumulation of damaged mitochondria and eventually inducing ferroptosis. Furthermore, the influence of DFIQ on the effects of clinical FIs, such as sorafenib, was evaluated, and DFIQ was discovered to sensitize NSCLC cells to sorafenib and promote ferroptosis.This study indicates that DFIQ not only promotes NSCLC apoptosis but also sensitizes cells to ferroptosis by disrupting autophagic flux, leading to accumulation of dysfunctional mitochondria and thus to ferroptosis. Ferroptosis is a novel therapeutic target in cancer therapy. DFIQ shows the potential to enhance the effects of FIs in NSCLC and act as a potential therapeutic adjuvant in ferroptosis-mediated therapy.© 2023. BioMed Central Ltd., part of Springer Nature.