Regulation of ferroptosis ameliorates silica nanoparticle-induced lung injury by inhibiting NCOA4-mediated ferritinophagy.

The massive global output and extensive application of silica nanoparticles (SiNPs) raise great human health concerns, especially in the lungs since the respiratory tract is a major portal for NPs entry. Emerging evidence has revealed that SiNPs cause pulmonary impairments, but the underlying mechanism remains elucidated. In this study, we clarify the role of ferroptosis in SiNPs-induced pulmonary toxicity and elucidate its molecular mechanism. First, the Wistar rats were administered to SiNPs (10 mg/kg·bw) with or without ferrostatin-1 (a well-known inhibitor of ferroptosis, shorted as Fer-1,1.0 mg/kg·bw). Results revealed that SiNPs induced impairments in lung function and histopathology by inducing ferroptosis, and the use of ferrostatin-1 alleviated the onset of ferroptosis and lung injury by SiNPs. In particular, the excessive activation of NCOA4 was involved in the ferroptotic process in response to SiNPs. In vitro, SiNPs generated intracellular Fe accumulation, ROS generation, and GPX4 depletion in the human bronchial epithelial cells (16HBE). By contrast, the inhibition of NCOA4 using the RNAi technique protected cells against these phenomena by SiNPs, hinting that SiNPs-induced ferroptosis was dependent on NCOA4-mediated ferritinophagy. Also, the inhibition of ferroptosis or NCOA4-mediated ferritinopathy could protect lung cells/tissue from apoptosis. In conclusion, our data indicated that ferroptosis via the NCOA4-mediated ferritinopathy pathway was a novel and critical mechanism of SiNP-induced lung injury. Of note, we highlight the therapeutic potential of suppressing ferritinopathy or ferroptosis for the management of SiNPs' toxicity.