Nrf2 Protects Against Lipoteichoic Acid-Induced Acute Lung Injury By Suppressing SLC24A2-Mediated Ferroptosis

Acute lung injury (ALI) is a severe inflammatory syndrome characterized by epithelial and endothelial injury, increased pulmonary vascular permeability, and impaired gas exchange. ALI often involves ferroptosis, an iron-dependent form of oxidative cell death. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of antioxidant defenses, but its role in ALI-related ferroptosis is not well understood. In this study, NRF2 knockout (KO) mice were utilized for transcriptomic analysis to investigate the role of NRF2 in ALI. NRF2 deficiency significantly exacerbated lung injury and ferroptosis, and upregulated the expression of the calcium transporter gene solute carrier family 24 member 2 (SLC24A2). Calcium overload was closely associated with increased SLC24A2 expression and contributed to the development of ferroptosis. These findings were validated in vitro: knockdown of NRF2 in lung epithelial cells enhanced susceptibility to ferroptosis, whereas overexpression of NRF2 attenuated ferroptotic cell death. Conversely, silencing SLC24A2 reduced intracellular calcium overload and suppressed ferroptosis. These results suggest that there may be a regulatory axis between NRF2 and SLC24A2, which has a potential association with inflammation and ferroptosis signals related to acute lung injury (ALI). However, further studies are required to clarify the causal relationship and its consistency across different models, thereby evaluating the feasibility of this axis as a potential therapeutic target.