3,3′-diindolylmethane induces ferroptosis and inhibits proliferation in non-small-cell lung cancer through the AHR/NRF2/GPX4 axis

作者：Lin Guo, Jia Zhang, Yongping Li, Yuqiang Li, Yuehong Gao, Jiali Huang, Jie Li, Jing Li, Wenshu Chai, Yubin Li, Yubin Li · 发表于：Discover Oncology · 年份：2025 · DOI：10.1007/s12672-025-02096-z · 被引用次数：8 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、MicroRNA in disease regulation

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 2+ , 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 treatm...