MAO-A inhibition alleviates sepsis-driven lung injury via Nrf2/HO-1 pathway activation and suppression of pyroptosis.

Extensive research has highlighted the involvement of excessive oxidative stress and pyroptosis in sepsis-caused acute lung injury (ALI). The present investigation delves into the potential role of Monoamine oxidase A (MAO-A) in this pathological process. Analyzing Gene Expression Omnibus (GEO) datasets alongside clinical samples revealed a significant upregulation of MAO-A in sepsis patients. To further elucidate this, cecal ligation puncture (CLP)-induced ALI were established in C57BL/6 mice. Additionally, human alveolar epithelial cells (HPAEpiC) treated with MAO-A inhibitor RO11-11639 were subjected to lipopolysaccharide (LPS) stimulation in vitro. The in-vivo experiments demonstrated that RO11-11639 mitigated CLP-induced ALI, significantly reducing pulmonary oxidative stress, inflammation and pyroptosis in lung tissue. Biochemical quantification revealed significant suppression of both oxidative stress biomarkers reactive oxygen species (ROS), malondialdehyde (MDA) and key inflammatory markers interleukin (IL)-1β, IL-16. Consistent with these findings, the in-vitro model confirmed that RO11-11639 reduced ROS and MDA accumulation, and inflammation in HPAEpiC, in response to LPS stimulation. Moreover, functional rescue analysis delineated the nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway as the critical mediator of RO11-11639's dual antioxidant and anti-pyroptosis activities in HPAEpiC. Mechanistically, MAO-A inhibition promoted the nuclear translocation of Nrf2, thereby activating the downstream regulatory proteins HO-1, quinone oxidoreductase 1 (NQO-1) and glutathione s-transferase (CST). These data cumulatively indicate that pharmacological targeting of MAO-A may offer therapeutic benefits in septic ALI by attenuating pathophysiological processes involving oxidative damage and inflammasome-mediated pyroptosis.