Hypoxia-driven ferroptosis escape mediates lung injury induced by nickel-refining fumes via oxygen-sensing signaling PHD1/HIF-1α.

Nickel exposure increases the risk of lung cancer; however, the mechanisms underlying nickel-induced oncogenic cell death remain unclear. While ferroptosis is linked to lung cancer, its role in nickel-induced malignant transformation is not well understood. We simulated long-term exposure of human bronchial epithelial cells (Beas-2B cells) to nickel-refining fumes (NiRF) from a smelter and found that NiRF exposure induced their malignant transformation. Ferroptosis was inhibited in these transformed cells (2B-NiRF cells), a phenomenon also observed in NiRF-exposed mouse lung tissue. Treatment of 2B-NiRF cells with ferroptosis inducers and inhibitors indicated that ferroptosis suppresses their malignant phenotype. Transcriptome analysis of 2B-NiRF cells revealed enrichment in hypoxia and HIF-1 signaling pathways. Mechanistically, the NiRF-induced hypoxic microenvironment inactivates prolyl hydroxylase domain protein 1 (PHD1), stabilizing hypoxia-inducible factor-1α (HIF-1α), which coordinates the transcriptional program to maintain 2B-NiRF cells in a ferroptosis-resistant state. Overexpression of PHD1 inhibits HIF-1α and its downstream angiopoietin-like protein 4 (ANGPTL4)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, thereby restoring sensitivity to ferroptosis in 2B-NiRF cells; knockdown of ANGPTL4 similarly modulates sensitivity to ferroptosis. This underscores the crucial role of the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis in ferroptosis-mediated NiRF-induced malignant transformation. The NiRF-exposed mouse model further confirms that in vivo expression of the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis is dysregulated. In conclusion, this study reveals a novel regulatory cascade in which NiRF inhibits cellular ferroptosis via the PHD1/HIF-1α/ANGPTL4/JAK2/STAT3 axis, thereby inducing malignant transformation of cells, providing potential targets for occupational lung cancer risk management against ferroptosis.