SLC38A1 Inhibits Ferroptosis of Alveolar Type II Epithelial Cells in Acute Lung Injury by Promoting Autophagic Degradation of Divalent Metal Transporter 1 (DMT1): an In Vivo and In Vitro Study

Recent studies have highlighted the relationship between ferroptosis in type II alveolar epithelial cell (ATII cell) and acute lung injury (ALI). Solute carrier family 38 member 1 (SLC38A1) is a member of the SLC38 gene family, expressed in the lung, and plays a crucial role in cellular processes. To explore the beneficial effects of SLC38A1 on ATII cell damage in Acute lung injury (ALI) from the perspectives of ferroptosis. Acute lung injury was established by intratracheal administration of lipopolysaccharide (LPS) in C57BL/6 mice for 24 hours. SLC38A1 overexpression was attained via adeno- associated virus serotype 6 (AAV6) transfection. Primary type II alveolar epithelial cell (ATII cell) were transfected with lentiviral vectors (LV) encoding SLC38A1, DMT1, shSLC38A1, shULK1, and shHSP90. Lung damage was assessed by TUNEL staining and pathological staining. Protein expression and interactions were assessed by western blotting and immunoprecipitation. SLC38A1 overexpression alleviated LPS-induced injury and inflammation by inhibiting oxidative stress and mitochondrial dysfunction in mice and ATII cells. Further results demonstrated that SLC38A1 overexpression inhibited ferroptosis, which was derived from promoting the degradation of Divalent Metal Transporter 1 (DMT1). SLC38A1 promoted the interactions among DMT1, HSP90, HSC70 and Lamp-2a, enhanced the lysosomal translocation of DMT1, and thereby intensified the chaperone-mediated autophagy (CMA) of DMT1. DMT1 overexpression accentuated LPS-induced lung injury and ATII cells injury, but the effects were relieved by SLC38A1 overexpression. SLC38A1 promotes DMT1 degradation through CMA, thereby inhibiting ferroptosis and improving lung injury. Consequently, we propose that SLC38A1 might serve as a potential therapeutic target and early diagnostic marker for ALI.