Nickel oxide nanoparticles induce apoptosis and ferroptosis in airway epithelial cells via ATF3

Exposure to nickel oxide nanoparticles (NiONPs), which have been widely produced and applied in industry, leads to adverse pulmonary and systemic effects. The aim of this study is to investigate the involvement of apoptosis and ferroptosis in NiONPs-induced acute lung injury (ALI). Intratracheal instillation of NiONPs into mice elevated the levels of pro-inflammatory cytokines, neutrophils, and proteins in the bronchoalveolar lavage fluid, and triggered apoptosis and ferroptosis in the lung tissues. Consistently, NiONPs-induced apoptosis and ferroptosis were observed in in vitro experiments using human lung epithelial cells. Activating transcription factor 3 (ATF3), a stress-inducible transcription factor, was upregulated by NiONPs exposure in both murine lung tissues and human lung epithelial cells. Moreover, human lung epithelial cells with ATF3 deficiency exhibited a lower level of apoptosis and ferroptosis when exposed to NiONPs. Collectively, our findings demonstrated that ATF3 was responsive to NiONPs exposure, and promoted NiONPs-induced apoptosis and ferroptosis in lung epithelial cells, indicating that ATF3 is a potential biomarker and therapeutic target for NiONPs-associated ALI.

Automated summary

This study investigated the role of apoptosis and ferroptosis in nickel oxide nanoparticles (NiONPs)-induced acute lung injury (ALI). The findings showed that NiONPs exposure led to apoptosis and ferroptosis in lung tissues and elevated levels of pro-inflammatory cytokines, neutrophils, and proteins in bronchoalveolar lavage fluid. Further experiments revealed that NiONPs exposure upregulated the expression of activating transcription factor 3 (ATF3) in murine lung tissues and human lung epithelial cells, and cells lacking ATF3 exhibited lower levels of apoptosis and ferroptosis when exposed to NiONPs. These results suggest that ATF3 may serve as a potential therapeutic target and biomarker for NiONPs-associated ALI.