Sirt4 Overexpression Modulates the JAK2/STAT3 and PI3K/AKT/mTOR Axes to Alleviate Sepsis-Induced Acute Lung Injury

Background Sepsis-induced acute lung injury (ALI) is a severe organ dysfunction characterized by lung inflammation and apoptosis. The mechanisms underlying sepsis-induced ALI remain poorly understood. Here, we determined the effects of sirtuin 4 (SIRT4) on sepsis-induced ALI. Methods Lipopolysaccharide (LPS)-induced injury cell and cecal ligation and puncture (CLP) animal models were established. Overexpression vectors and lentiviral transfections were used to upregulate SIRT4 expression. Lung cell apoptosis, inflammation, and the levels of associated factors were evaluated. Changes in the PI3K/AKT/mTOR and JAK2/STAT3 pathways were measured, and their potential involvement was examined using LY294002 (PI3K inhibitor), 740 Y-P (PI3K agonist), AG490 (JAK2 inhibitor), and coumermycin A1 (JAK2 agonist). Results Lower SIRT4 expression was observed in LPS-exposed A549 cells and CLP rats. In LPS-induced A549 cells, Sirt4 overexpression enhanced cell viability, resisted apoptosis, restored the expression of apoptosis-associated proteins (HMB1, cleaved CASP3, BAX, and BCL), and reduced the secretion of pro-inflammatory cytokines (IL-6, IL-1 beta, and TNF-alpha). In CLP rats, Sirt4 overexpression prolonged survival time, alleviated lung histopathological damage, reduced pulmonary edema, mitigated lung infection, decreased lung apoptosis, and lowered serum levels of inflammatory cytokines. Furthermore, Sirt4 overexpression blocked JAK2/STAT3/AKT/mTOR phosphorylation. 740 Y-P and coumermycin A1 reversed the protective effects of Sirt4 overexpression in LPS-treated A549 cells, resulting in decreased cell viability and increased apoptosis. LY294002 and AG490 enhanced the protective effects of Sirt4 overexpression in LPS-treated A549 cells. Conclusion SIRT4 alleviates sepsis-induced ALI by inhibiting JAK2/STAT3/PI3K/AKT/mTOR signaling. Upregulating SIRT4 expression may serve as an innovative therapeutic approach for lung injury management in sepsis.