Cadmium Inhibits Proliferation of Human Bronchial Epithelial BEAS-2B Cells Through Inducing Ferroptosis via Targeted Regulation of the Nrf2/SLC7A11/GPX4 Pathway

Cadmium (Cd)-induced pulmonary toxicity is closely associated with ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation (LPO). Luteolin (Lut) is a natural flavonoid compound that exists in many plants. In this study, we used human bronchial epithelial BEAS-2B cells to explore the impact of ferroptosis in the inhibition of Cd-induced BEAS-2B cells proliferation. BEAS-2B cells were exposed to Cd (5 μM) with/without Lut (10 μM), ferroptosis modulators (Ferrostatin-1 (Fer-1)/Erastin), or nuclear factor erythroid 2-related factor 2 (Nrf2) regulators (tert-butylhydroquinone (TBHQ)/ML385). Viability, iron content, reactive oxygen species (ROS), LPO, mitochondrial membrane potential (MMP), and glutathione peroxidase (GSH-PX) activity were assessed. Exposure to Cd significantly decreased cell viability, increased intracellular iron levels, ROS production, and LPO activity, while simultaneously reducing MMP and GSH-PX activity. Fer-1 mitigated Cd-induced cytotoxicity, but Erastin intensified these effects. Mechanistically, Cd exposure suppressed the Nrf2/Solute Carrier Family 7 Member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway, which plays a crucial role in maintaining redox homeostasis. Activation of Nrf2 using TBHQ mitigated oxidative stress and upregulated the expression of key proteins within this pathway, while inhibition of Nrf2 with ML385 exacerbated cellular damage. Notably, Lut treatment could significantly alleviate Cd-induced cytotoxicity, oxidative stress, and downregulation of Nrf2/SLC7A11/GPX4 proteins. These findings demonstrate that ferroptosis is a critical mechanism underlying Cd-mediated lung epithelial injury and identify Lut as a promising therapeutic candidate via its activation of Nrf2-driven antioxidant defense mechanisms. This study provides novel insights into molecular targets for the prevention and treatment of Cd-associated pulmonary disorders.