RTA408 alleviates lipopolysaccharide-induced acute lung injury via inhibiting Bach1-mediated ferroptosis

The approved traditional Asian medicine RTA408 (Omaveloxolone) has demonstrated potent anti-inflammatory properties in the treatment of Friedreich's ataxia. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains poorly understood. This study aims to evaluate the effect of RTA408 on LPS-induced ALI and elucidate its underlying mechanisms. In this study, in vivo experiments demonstrated that RTA408 significantly ameliorated LPS-induced mouse ALI, characterized by reduced pathological damage and neutrophil infiltration as well as decreased lung edema of murine lung tissues. Moreover, LPS administration induced ferroptosis in ALI mice, evidenced by increased MDA levels, reduced GSH and SOD activity, and decreased expression of ferroptosis repressors (GPX4 and SLC7A11), whereas RTA408 reversed these changes. Consistently, RTA408 reduced ferroptosis and improved cell damage in LPS-stimulated MLE-12 cells, as evidenced by decreased ROS and MDA levels, increased SOD, GSH activity and ferroptosis repressors expression. Meanwhile, the protective effective of RTA408 on LPS-induced oxidative damage was blocked by ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistic studies demonstrated that RTA408 inhibited the expression and nuclear translocation of Bach1, and the anti-ferroptosis effect was diminished by Bach1 siRNA or Bach1 knockout (Bach1(-/-)) mice. Furthermore, Bach1(-/-) mice exhibited attenuated ALI induced by LPS compared to wild-type (WT) mice, and the protective effect of RTA408 on LPS-challenged ALI was not observed in Bach1(-/-) mice. In conclusion, our data suggested that RTA408 alleviates LPS-induced ALI by interfering Bach1-mediated ferroptosis and might be a novel candidate for LPS-induced ALI/ARDS therapy.