近年来，通过触发细胞铁死亡来抑制肿瘤细胞活动已成为研究的热点。发展通用的靶向纳米治疗可能为非侵入性应用带来新的思路。目前，铁氧化物纳米颗粒（IONP@PTX）负载紫杉醇（PTX）在不同类型的肿瘤中通用应用潜在机制尚不清楚。本研究旨在制备IONP@PTX进行靶向癌症治疗，并进一步探索其对NCI‑H446人类小细胞肺癌和脑M059K恶性胶质母细胞瘤细胞系抑制作用的潜在机制。首先，使用CCK‑8试验确定细胞存活率，然后评估药物组合互作效果的联合指数。使用DCFH‑DA荧光探针和C11‑BODIPY™荧光探针监测细胞内活性氧自由基（ROS）和脂质过氧化物水平。此外，进行了Western blotting实验，以确定自噬和铁死亡相关蛋白的表达。实验结果显示，与IONP单独治疗、PTX单独治疗或IONP+PTX相比，IONP@PTX对两种细胞类型的存活率具有协同作用，同时总铁离子浓度、ROS水平和脂质过氧化物水平显著增加。IONP@PTX显著增加了两种细胞系中自噬相关蛋白Beclin 1和组蛋白去乙酰化酶 6（HDAC6）的表达（P<0.05），增加了NCI‑H446细胞中轻链 3（LC3）‑II/I的表达（P<0.05），并降低了M059K细胞中周贮 1（p62）的表达（P<0.05）。此外，雷帕霉素的添加增强了IONP@PTX诱导Beclin 1、LC3‑II/I和HDAC6的上调，以及两种细胞系中mTORC1蛋白的下调（P<0.05）。此外，雷帕霉素增强了IONP@PTX诱导NCI‑H446细胞中p62蛋白的下调（P<0.05），这表明IONP@PTX通过自噬最可能诱导铁死亡。综上所述，本研究结果显示，IONP与PTX协同诱导自噬途径下的铁死亡。

In recent years, inhibiting tumor cell activity by triggering cell ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non‑invasive applications. Currently, the potential mechanism underlying the universal application of paclitaxel (PTX)‑loaded iron oxide nanoparticles (IONP@PTX) to different types of tumors is unclear. The present study aimed to prepare IONP@PTX for targeted cancer therapy and further explore the potential mechanisms underlying the inhibitory effects of this material on the NCI‑H446 human small cell lung cancer and brain M059K malignant glioblastoma cell lines. First, a CCK‑8 assay was performed to determine cell viability, and then the combination index for evaluating drug combination interaction effect was evaluated. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were monitored using a DCFH‑DA fluorescent probe and a C11‑BODIPY™ fluorescent probe, respectively. Furthermore, western blotting assay was performed to determine the expression of autophagy‑ and iron death‑related proteins. The experimental results showed that, compared with either IONP monotherapy, PTX monotherapy, or IONP + PTX, IONP@PTX exerted a synergistic effect on the viability of both cell types, with significantly increased total iron ion concentration, ROS levels and lipid peroxidation levels. IONP@PTX significantly increased the expression of autophagy‑related proteins Beclin 1 and histone deacetylase 6 (HDAC6) in both cell lines (P<0.05), increased the expression of light chain 3 (LC3)‑II/I in NCI‑H446 cells (P<0.05) and decreased that of sequestosome1 (p62) in M059K cells (P<0.05). Moreover, the addition of rapamycin enhanced the IONP@PTX‑induced the upregulation of Beclin 1, LC3‑II/I and HDAC6 and the downregulation of mTORC1 protein in both cell lines (P<0.05). Moreover, rapamycin enhanced the IONP@PTX‑induced downregulation of p62 protein in NCI‑H446 cells (P<0.05), suggesting that IONP@PTX induces ferroptosis, most likely through autophagy. Collectively, the present findings show that IONP works synergistically with PTX to induce ferroptosis via the autophagic pathway.