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<p>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&#xa0;kcal/mol) and PI3K (-7.619&#xa0;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.</p>

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Hesperetin alleviates sepsis-associated acute respiratory distress syndrome via the PI3K/Akt/PTEN axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Huozhao Ruan,
  • Dong Yang,
  • Niannian Wang,
  • Jinhai Liu,
  • Lingyu Huang

摘要

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.