Guo Lin, Zhang Jia, Li Yuqiang, Gao Yuehong, Huang Jiali, Liu Mengru, Li Jing, Chai Wenshu, Li Yubin
Department of Respiratory Medicine, the First Affiliated Hospital of Jinzhou Medical University, No.2, Section 5Renmin Street, Guta District, Jinzhou City, 121001, Liaoning Province, China.
Department of Hematology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, China.
Discov Oncol. 2025 Mar 18;16(1):344. doi: 10.1007/s12672-025-02096-z.
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. In lung cancer, AHR activation stimulates cancer cell proliferation and promotes tissue invasion and metastasis, and targeting the AHR pathway is an effective way to prevent and treat lung cancer. In lung cancer, AHR binds to the NRF2 promoter region to promote carcinogenesis, but treatment research based on AHR/NRF2 pathway is insufficient. 3,3'-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, is a modulator of AHR. In this study, We investigated the medicinal value of DIM in NSCLC (non-small cell lung cancer) by in vivo and in vitro experiments and explored the underlying mechanisms. In vitro studies showed that DIM inhibited the viability of NSCLC and induced apoptosis and cycle arrest in cancer cells. DIM inhibited the migration and invasion of NSCLC cells by reversing the epithelial-mesenchymal transition. DIM induced ferroptosis in NSCLC cells; increased cellular Fe, ROS (reactive oxygen species), and MDA; decreased cellular GSH, AHR, NRF2, and GPX4; and disrupted the mitochondrial membrane potential. The effect of DIM-induced ferroptosis can be reversed by the AHR receptor antagonist CH-223191, ferroptosis inhibitor Fer-1, and ROS scavenger NAC. Overexpression of NRF2 reversed DIM-induced ferroptosis. Identical results were obtained in a nude mouse xenograft model. In summary, we have confirmed that DIM has significant potential in the treatment of non-small cell lung cancer. DIM induces cancer cell ferroptosis through the AHR/NRF2/GPX4 axis. These findings provide experimental basis for DIM treatment and future clinical research in non-small cell lung cancer.
芳烃受体（AHR）是一种配体激活的转录因子。在肺癌中，AHR激活会刺激癌细胞增殖，并促进组织侵袭和转移，靶向AHR信号通路是预防和治疗肺癌的有效途径。在肺癌中，AHR与NRF2启动子区域结合以促进肿瘤发生，但基于AHR/NRF2信号通路的治疗研究尚不充分。3,3'-二吲哚甲烷（DIM）是一种从十字花科蔬菜中提取的活性植物化学衍生物，是AHR的调节剂。在本研究中，我们通过体内和体外实验研究了DIM在非小细胞肺癌（NSCLC）中的药用价值，并探索了其潜在机制。体外研究表明，DIM抑制NSCLC的活力，并诱导癌细胞凋亡和细胞周期停滞。DIM通过逆转上皮-间质转化抑制NSCLC细胞的迁移和侵袭。DIM诱导NSCLC细胞发生铁死亡；增加细胞内铁、活性氧（ROS）和丙二醛；降低细胞内谷胱甘肽、AHR、NRF2和谷胱甘肽过氧化物酶4（GPX4）；并破坏线粒体膜电位。AHR受体拮抗剂CH-223191、铁死亡抑制剂Fer-1和ROS清除剂NAC可逆转DIM诱导的铁死亡效应。NRF2的过表达可逆转DIM诱导的铁死亡。在裸鼠异种移植模型中也获得了相同的结果。综上所述，我们证实了DIM在治疗非小细胞肺癌方面具有显著潜力。DIM通过AHR/NRF2/GPX4轴诱导癌细胞铁死亡。这些发现为DIM治疗非小细胞肺癌及未来的临床研究提供了实验依据。
