Mechanism of endoplasmic reticulum stress-induced endothelial cell ferroptosis in trichloroethylene-induced mouse kidney injury.

Trichloroethylene (TCE) is widely employed as a cleaning agent in industrial settings. Occupational exposure to TCE can lead to occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Our previous research has identified damage to renal vascular endothelial cells (ECs) in both OMDT patients and TCE-sensitized mice; however, the underlying mechanisms remain insufficiently understood. Methods: This study aims to elucidate the role of endoplasmic reticulum stress (ERS)-induced ECs ferroptosis in TCE-induced renal injury by developing a TCE-sensitization mouse model. Our findings indicate that ferroptosis in renal ECs is associated with TCE-induced kidney damage, and the ferroptosis inhibitor Fer-1 can mitigate this injury. Notably, ERS can modulate TCE-induced ECs ferroptosis. The PERK inhibitor GSK2606414 can suppress ferroptosis via the Nrf2/HO-1 signaling pathway and reduce trichloroethylene-induced renal injury. In conclusion, TCE sensitization activates ERS through the PERK/eIF2α/ATF4 pathway, with PERK subsequently mediating ferroptosis of renal vascular endothelial cells via the Nrf2/HO-1 signaling pathway, thereby contributing to TCE-related immune kidney injury.