BAP31 attenuates acute lung injury by inhibiting ferroptosis through activation of the AKT/GSK3β/Nrf2 pathway in the alveolar epithelial cells

Abstract Background: Ferroptosis plays an important role in the progression of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Although B-cell receptor-associated protein 31 (BAP31) has been shown to mitigate lung inflammation and oxidative stress, its involvement in ferroptosis during ALI remains unclear. This study aimed to investigate the relationship between BAP31 and ferroptosis in ALI. Methods: To explore the role of BAP31 in LPS-induced ALI, we established an ALI model by administering LPS directly into the lungs of both wild-type mice and transgenic mice overexpressing BAP31 , followed by collection of lung tissues 24 h post-injection for transcriptomic analysis. Besides, in vivo and in vitro experiments were conducted to evaluate BAP31’s effect on ferroptosis in LPS-induced ALI and explore the underlying mechanism. Results: Our findings show a significant reduction in BAP31 expression in ALI, coinciding with increased ferroptosis. Overexpression of BAP31 reduced LPS-induced inflammation and oxidative stress. RNA sequencing revealed that ferroptosis is a central factor in BAP31’s protective effects. BAP31 activates the protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) pathway, promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently induced the expression of ferroptosis-related genes such as GPX4 and HMOX1 . Inhibition of Nrf2 nullified BAP31’s antioxidant and antiferroptotic effects, highlighting the AKT/GSK3β/Nrf2 pathway as the key mechanism. Conclusion: BAP31 mitigates ALI by inhibiting ferroptosis through activation of the AKT/GSK3β/Nrf2 pathway.