Hot air injures human alveolar epithelial cells through ERK1/2 signaling-mediated ferroptosis.

Inhalation lung injury is an acute pulmonary impairment resulting from inhalation of hot air and/or toxic gases. However, the molecular mechanisms involved in hot air-induced heat stress (HS) response of alveolar epithelial cells are not fully understood. In this study, employing a cell heat loading device, we found that HS at 50 °C resulted in significant ferroptosis and injury of human alveolar epithelial cells (BEAS-2B cells), supported by increased lipid peroxidation, reactive oxygen species (ROS), and decreased ferritin heavy chain 1 (FTH1), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11). Ferrostatin-1 (Fer-1), a targeted inhibitor of ferroptosis, could suppress HS-induced ferroptosis and injury of BEAS-2B cells. Moreover, HS activated extracellular signal-regulated kinase 1/2 (ERK1/2) in BEAS-2B cells. Nevertheless, blockage of ERK1/2 activation by U0126, an inhibitor of ERK1/2 phosphorylation, repressed HS-induced ferroptosis and injury of BEAS-2B cells. Taken together, this study demonstrates that HS injures alveolar epithelial cells through ERK1/2 signaling-mediated ferroptosis, which provides a novel potential strategy for the treatment of HS-induced inhalation lung injury.