Menaquinone-4 Alleviates Sepsis-Associated Acute Lung Injury via Activating SIRT3-p53/SLC7A11 Pathway

Nan Gao,1,2 Xiao-Yu Liu,1,2 Jie Chen,1,2 Tian-Peng Hu,1,2 Yu Wang,2,3 Guo-Qiang Zhang2 1China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 3Graduate School, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Guo-Qiang Zhang, Department of Emergency, China-Japan Friendship Hospital, Beijing, 10029, People’s Republic of China, Tel +8613701054849, Email [email protected]: Sepsis-associated acute lung injury (SI-ALI) is triggered by various direct or indirect noncardiogenic factors affecting the alveolar epithelium and capillary endothelial cells. Menaquinone-4 (MK-4), a major component of vitamin K, plays a crucial role as an antioxidant by effectively neutralizing reactive oxygen species (ROS) and safeguarding critical biomolecules from oxidative harm within cells. However, the specific mechanisms and clinical implications of MK-4 in SI-ALI are unclear and require further study.Methods: Cecal ligation and puncture (CLP) surgery is a commonly used method to induce sepsis in C57BL/6N wild-type mice, and the mice were administered MK-4 at a dosage of 200 mg/kg/day and 3-TYP at 5 mg/kg/day via intraperitoneal injection for 3 days, or erastin (5 mg/kg) 0.5 hours before CLP surgery. The mice were sacrificed 24 hours after CLP surgery, and blood and lung tissue samples were collected. Pathological changes in the lung tissue and oxidative stress levels were detected. The expression levels of Sirt3, acetylated lysine, p53, SLC7A11 ALOX12 and ferroptosis-related proteins were determined. ligation and puncture (CLP)Results: In this study, we observed that the lung inflammation was associated with reduced Sirt3 expression and increased acetylated lysine levels. The progression of SI-ALI was mitigated by MK-4 through its role in upregulating Sirt3 expression. MK-4 achieved antioxidant effects by downregulating ROS and inflammatory factor levels. Mechanistically, MK-4 inhibited the p53/SLC7A11 signalling pathway in ferroptosis by inhibiting the acetylation of p53, independent of p53 levels. In addition, MK-4 inhibited ferroptosis independent of GPX4. These findings indicate that MK-4 is a promising novel therapeutic agent for treating SI-ALI and possibly sepsis.Conclusion: These experiments revealed that MK-4 acts as a ferroptosis suppressor, increasing the expression of Sirt3, inhibiting the p53/SLC7A11 signalling pathway, and reducing oxidative stress and inflammatory responses, thereby exerting a protective effect against ALI in sepsis.Keywords: MK-4, Sirt3, acetylation, p53, ferroptosis, SI-ALI