Ferroptosis as a central mechanism in inhaled tris(1-chloro-iso-propyl) phosphate (TCIPP)-induced lung injury: Associations with pyroptosis and mitochondrial dynamic imbalance.

Tris(1-chloro-iso-propyl) phosphate (TCIPP) emerged as the predominant organophosphorus flame retardants (OPFRs) in both dust and air environments. This study investigated its respiratory toxicity using mouse inhalation model. Molecular docking and dynamics simulations revealed that TCIPP could binds to glutathione peroxidase 4 (GPX4) with an affinity of -5.3098 kcal/mol, stabilizing the protein conformation. Inhalation TCIPP exposure (34 μg/m3 for 1 h) significantly reduced GPX4 expression and GSH levels in lung tissue. Histopathological examination indicated severe pulmonary injury, including inflammatory cell infiltration, alveolar wall thickening and apoptosis after TCIPP inhalation. Besides, DHE staining revealed that the ROS level increased by 94.7% in the lung after TCIPP exposure. Meanwhile, the results revealed a 50.7% increase in lung iron content (Fe2+), along with elevated ferroptosis markers (p53, Transferrin Receptor 1 (TFR1)) and reduced FTH1 levels following TCIPP inhalation. These effects were counteracted by the ferroptosis inhibitor Fer‑1 (0.8 mg/kg), which also attenuated pathological damage, ROS accumulation, and NLRP3‑mediated pyroptosis. Concurrently, electron microscopy analysis demonstrated mitochondrial cristae membrane disruption and shrinkage, accompanied by dysregulated expression of mitochondrial dynamics regulators (down‑regulated Mfn1/2 and up‑regulated Drp1), all of which were reversed by Fer‑1. Collectively, the results indicate that TCIPP inhalation induces GPX4‑dependent ferroptosis, promoting inflammatory responses and mitochondrial imbalance, ultimately driving respiratory toxicity. Ferroptosis thus represents a potential therapeutic target for organophosphorus flame retardant‑associated lung injury, which may aid in biomarker discovery for related pulmonary diseases.