IRGM Deficiency Exacerbates Sepsis-Induced Acute Lung Injury by Inhibiting Autophagy Through the AKT/mTOR Signaling Pathway

Na Guo,1,* Yu Xia,1,* Nannan He,1 Huixin Cheng,1 Lei Zhang,2 Jian Liu1,2 1The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China; 2Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Liu; Lei Zhang, Email [email protected]; [email protected]: Sepsis is a life-threatening condition characterized by organ dysfunction due to an impaired immune response to infection. The lungs are highly susceptible to infection, often resulting in acute lung injury (ALI). The immune-related GTPase M (IRGM) and its murine homolog Irgm1 mediate autophagy and are implicated in inflammatory diseases, yet their roles in sepsis-induced ALI remain unclear.Methods: We used RNA sequencing and bioinformatics to explore IRGM regulation. Sepsis-induced ALI was modeled in mice using cecal ligation and puncture (CLP). An in vitro model was created by stimulating A549 cells with lipopolysaccharide (LPS).Results: In A549 cells, LPS treatment induced upregulation of IRGM expression and enhanced autophagy levels. IRGM knockdown exacerbated LPS-induced ALI, characterized by suppressed autophagy and increased apoptosis, along with significantly elevated levels of p-AKT and p-mTOR. Further investigation revealed that treatment with the AKT inhibitor MK2206 effectively reversed the autophagy inhibition caused by IRGM knockdown and reduced apoptosis. These findings suggest that the AKT/mTOR signaling pathway plays a crucial role in IRGM-mediated protection against sepsis-related ALI.Conclusion: This study identifies the protective role of IRGM in sepsis-induced ALI and reveals that IRGM mitigates ALI by promoting autophagy through inhibition of the AKT/mTOR pathway. These findings provide insights into the pathogenesis of sepsis-related ALI and highlight IRGM as a potential therapeutic target.Keywords: sepsis-induced acute lung injury, IRGM, AKT/mTOR signaling pathway, autophagy