Chrysin reshapes ferroptosis sensitivity to reverse nickel refining fumes-induced lung injury via the miR-210/ANGPTL4 signaling axis mediated by the PHD1/HIF-1α pathway.

Nickel refining fumes (Ni) are recognized occupational pollutants that adversely affect workers' respiratory health; however, the specific molecular mechanisms underlying their induction of lung injury remain poorly understood. Chrysin, a flavonoid compound with established anticancer and antioxidant properties, has uncertain therapeutic effects on lung injury. This study aims to investigate the effects of chronic low-dose exposure to Ni on human bronchial epithelial cells (Beas-2B cells). After 180 days of continuous low-dose Ni treatment, the test cells exhibited pronounced characteristics of malignant transformation compared to the control group. Transcriptomic analysis indicated significant activation of hypoxia signaling pathways in the transformed cells (2B-Ni cells). Both cellular and animal experiments confirmed the presence of abnormal ferroptosis-related markers and a suppression of the ferroptosis process. Chrysin significantly suppresses 2B-Ni cell activity by inhibiting proliferation, invasion, and migration capabilities while inducing ferroptosis. Further studies demonstrate that Ni regulates the prolyl hydroxylase domain protein 1 (PHD1)/hypoxia-inducible factor-1α (HIF-1α)/microRNA-210 (miR-210)/angiopoietin-like protein 4 (ANGPTL4) pathway, facilitating escape from ferroptosis in Beas-2B cells and subsequent malignant transformation. Conversely, Chrysin regulates PHD1/HIF-1α-induced ferroptosis, resulting in increased intracellular MDA, total iron content, and lipid peroxidation levels. The addition of DMOG or CoCl2 can reverse this effect. In summary, this study confirms that the PHD1/HIF-1α/miR-210/ANGPTL4 pathway mediates Ni-induced suppression of ferroptosis, thereby promoting malignant transformation in Beas-2B cells. Conversely, chrysin mitigates Ni-induced lung injury by regulating PHD1/HIF-1α-induced ferroptosis in 2B-Ni cells. These findings offer essential theoretical support and potential targets for evaluating Ni's carcinogenic risk and developing ferroptosis-targeted anti-tumor therapies.