EIF4A3-mediated downregulation of circ_0073586 promotes cadmium-induced lung carcinogenesis through SRSF9-triggered GPX4-dependent ferroptosis resistance

Environmental heavy metal exposure represents a well-established etiological factor in pulmonary carcinogenesis. Although ferroptosis dysregulation contributes to Cadmium (Cd) induced pulmonary carcinogenesis, its precise molecular determinants remain elusive. Here, we demonstrated that Cd treatment (5 μM) induced EIF4A3-mediated downregulation of circ_0073586 in human bronchial epithelial (16HBE) cells, which functionally promoted malignant transformation. Intriguingly, we observed that ferroptosis was markedly suppressed in malignant transformed cells as the exposure duration increased, a suppression that was significantly reversed by circ_0073586 overexpression. Mechanistically, circ_0073586 acted as a molecular decoy for the RNA-binding protein SRSF9, thereby effectively suppressing GPX4-dependent cellular ferroptosis through the Wnt/β-catenin pathway. These findings were validated in vivo, where Cd-exposed murine models at 36 weeks exhibited concurrent downregulation of circ_0073586 and suppression of ferroptosis, with these changes showing a strong correlation. Thus, the study not noly reveals a critical crosstalk between metabolism-associated cell death and epigenetic regulation during Cd-induced pulmonary carcinogenesis, but also identifies potential molecular targets for intervention in heavy metal-associated lung cancer.