Background: Methicillin-resistant Staphylococcus aureus (MRSA) are a critical predisposing factor of sepsis in the clinic. As a product of human energy metabolism and immune response, itaconate can effectively reduce inflammation in the body. This research employed 4-octyl itaconate (4-OI) to illustrate that itaconate exerted anti-inflammatory effects to protect the body from acute lung injury (ALI) induced by MRSA. Methods: HE staining and immunohistochemistry are used to evaluate the MRSA-induced ALI in mice. WB and qPCR were used to verify the effect of 4-OI on inflammation and oxidative stress caused by MRSA. Molecular docking was used to verify the binding sites of 4-OI and Keap1. Results: We demonstrated that 4-OI treatment increased the survival ratio, attenuated the pathological damage, inhibited neutrophil infiltration, and reduced lung bacterial burden in the mouse MRSA pneumonia model. 4-OI decreased the expression of inflammatory factors by stimulating the Nrf2 in vivo and in vitro. Furthermore, 4-OI exerted its effect by promoting nuclear transport of Nrf2 in vitro. The results of molecular docking indicated that 4-OI bound to the pocket of Keap1 and exerted a stable interaction. Both Nrf2 inhibitors (ML385) and Nrf2^−/− mice abolished the protective effect of 4-OI on MRSA-induced inflammation both in vitro and in vivo. Conclusions: 4-OI prevents lung damage caused by MRSA bacteremia via activating Nrf2/ARE pathway.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA‐induced ALI (SA‐ALI) remains unclear. In this study, serum samples were collected from SA‐sepsis patients, and a SA‐ALI mouse model was established by grouping WT and Nrf2^−/− mice after 6 h of intraperitoneal injection. A cell model simulating SA‐ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA‐sepsis patients, negatively correlated with the severity of ALI. In SA‐ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation‐induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA‐ALI. The p‐Nrf2/total‐Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA‐treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual‐luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA‐ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Sepsis is a systemic inflammatory disease caused by severe infection, involving multiple organs in the body, with the lungs being the most susceptible, leading patients to develop acute lung injury (ALI). Mitoquinone Mesylate (MitoQ) is an antioxidant specifically designed to target mitochondria, and it has anti-aging and antioxidant properties. This study aimed to investigate the protective effects of MitoQ on sepsis-induced ALI and its mechanisms. C57BL/6 mice were used to establish the cecal ligation and puncture (CLP) model of sepsis and were orally administered or not administered MitoQ for two weeks. MitoQ effectively alleviated sepsis-induced lung tissue damage, inflammatory responses, oxidative stress, and apoptosis. Furthermore, MitoQ significantly inhibited oxidative stress and mitochondrial damage in pulmonary macrophages. Mechanistically, MitoQ upregulated the mRNA and protein levels of citrate synthase (CS) in lung tissues and pulmonary macrophages. Silencing the CS gene with siRNA significantly reduced the protective effects of MitoQ against oxidative stress, inflammation, and cell apoptosis. In conclusion, MitoQ alleviates sepsis-induced ALI by preserving mitochondrial function.