Department of Thoracic Surgery, Nanjing Chest Hospital, Nanjing 210029, P.R China.
Department of Thoracic Surgery, People's Hospital of Luhe District in Nanjing, Nanjing 210000, P.R China.
J Environ Pathol Toxicol Oncol. 2024;43(2):1-12. doi: 10.1615/JEnvironPatholToxicolOncol.2023049084.
This study aimed to investigate the underlying molecular mechanisms of transferrin receptor (TFR1) in non-small cell lung cancer (NSCLC). Histological analysis was performed using hematoxylin-eosin (HE) staining. The number of CD8+ T cell were determined by flow cytometry and immunofluorescence assays. mRNA levels were analyzed by qRT-PCR. Protein expression was detected by western blot. Ferroptosis was detected by using propidium iodide (PI) staining. Xenograft experiment was applied for determining tumor growth. The results showed that interferon (IFN)-γ plus iron dextran (FeDx) induced iron overload and the ferroptosis of NSCLC cells. Moreover, IFN-γ-mediated upregulation of TFR1 promoted ferritinophagy and tumor cell ferroptosis via blocking via blocking ferritin heavy chain 1 (FTH1)/ ferritin light chain (FTL) signaling. However, TFR1 knockout suppressed the ferroptosis of tumor cells. Furthermore, FeDx-mediated iron overload promoted the sensitivity of anti-programmed death ligand 1 (PD-L1) therapies. Clinically, TFR1 was downregulated in NSCLC patients. Low levels of TFR1 predicted decreased CD8+ T cells. Taken together, IFN-γ combined with iron metabolism therapies may provide a novel alternative for NSCLC.
本研究旨在探讨转铁蛋白受体（TFR1）在非小细胞肺癌（NSCLC）中的潜在分子机制。采用苏木精-伊红（HE）染色进行组织学分析。通过流式细胞术和免疫荧光法测定 CD8+T 细胞的数量。通过 qRT-PCR 分析 mRNA 水平。通过 Western blot 检测蛋白表达。通过碘化丙啶（PI）染色检测铁死亡。应用异种移植实验确定肿瘤生长。结果表明，干扰素（IFN）-γ 加铁右旋糖苷（FeDx）诱导 NSCLC 细胞铁过载和铁死亡。此外，IFN-γ 介导的 TFR1 上调通过阻断铁蛋白重链 1（FTH1）/铁蛋白轻链（FTL）信号促进 ferritinophagy 和肿瘤细胞铁死亡。然而，TFR1 敲除抑制了肿瘤细胞的铁死亡。此外，FeDx 介导的铁过载促进了抗程序性死亡配体 1（PD-L1）治疗的敏感性。临床上，TFR1 在 NSCLC 患者中下调。TFR1 水平低预示着 CD8+T 细胞减少。总之，IFN-γ 联合铁代谢治疗可能为 NSCLC 提供一种新的选择。
