Abstract

Sepsis-associated acute respiratory distress syndrome (ARDS) is a life-threatening condition marked by severe inflammation and oxidative stress, with limited therapeutic options. Hesperetin, a natural citrus flavonoid, has antioxidant and anti-inflammatory properties, but its molecular mechanisms in ARDS remain unclear. To explore the therapeutic potential and mechanisms of hesperetin in sepsis-associated ARDS using network pharmacology and in vitro experiments. Network pharmacology identified common targets of hesperetin and ARDS, followed by protein-protein interaction, Gene Ontology, and KEGG analyses to reveal hub targets and pathways. Molecular docking assessed binding affinities. In vitro, an LPS-induced MH-S alveolar macrophage model was used to evaluate hesperetin’s effects on cytokines, reactive oxygen species (ROS), apoptosis, and signaling, with Western blot analysis of PI3K-Akt modulation. Eighty-seven common targets were identified, including TNF, IL6, AKT1, and STAT3, enriched in the PI3K-Akt pathway. Docking confirmed strong affinities for AKT (-7.943 kcal/mol) and PI3K (-7.619 kcal/mol). Hesperetin reduced IL-1β, IL-6, TNF-α, ROS, and apoptosis, while increasing IL-10 and PTEN in a dose-dependent manner. Western blot showed inhibition of PI3K-Akt activation via PTEN upregulation. Hesperetin alleviates sepsis-associated ARDS through multi-target mechanisms, particularly the PTEN/PI3K-Akt axis, supporting its potential as a therapeutic agent.