SGK1 targets the GRN/AKT/mTOR pathway to alleviate sepsis-induced acute lung injury by inhibiting M1 polarisation through reduced fatty acid synthesis in macrophages

To investigate the role and mechanism of Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1) in macrophage regulation during sepsis-induced acute lung injury (ALI). SGK1 expression was measured in peripheral blood from patients with sepsis-induced acute respiratory distress syndrome (ARDS), and its association with disease severity and 28-day prognosis was analysed. An LPS-induced ALI mouse model was established, and LPS-treated RAW264.7 cells were used. Viral vectors were employed to upregulate or downregulate SGK1 expression. Macrophage polarisation, fatty acid metabolism and alterations in AKT/mTOR signalling were assessed via histology, flow cytometry, western blotting, transcriptomic and metabolomic analyses and co-immunoprecipitation. Peripheral blood SGK1 was significantly downregulated in patients with sepsis-associated ARDS, exhibiting negative correlations with inflammatory markers, organ function scores and 28-day mortality risk, demonstrating favourable diagnostic and prognostic value. SGK1 expression was similarly reduced in lung tissue from ALI mice, bone marrow-derived macrophages and LPS-stimulated RAW264.7 cells. SGK1 deficiency promoted M1 polarisation, pro-inflammatory cytokine secretion, AKT/mTOR activation and fatty acid synthesis, whereas SGK1 upregulation reversed these alterations. Integrated transcriptomic and metabolomic data indicated fatty acid biosynthesis as a key pathway regulated by SGK1. Mechanistically, our data support that SGK1 interacts with Granulin (GRN), is associated with reduced GRN protein stability, and is accompanied by suppression of AKT/mTOR activation, lipid synthesis and M1 polarisation. In vivo studies demonstrated that AAV-mediated SGK1 overexpression reduced inflammatory cell infiltration and cytokine levels, lowered lung injury scores and mitigated LPS-induced ALI. SGK1 mitigates sepsis-induced ALI by suppressing GRN/AKT/mTOR-dependent fatty acid synthesis and M1 macrophage polarization. SGK1 may serve as a promising biomarker candidate and therapeutic target for sepsis-induced ARDS. However, these findings require validation in larger, multicenter cohorts.