Scutellarin alleviates ferroptosis in cigarette smoke-induced chronic obstructive pulmonary disease via activation of the PI3K/AKT/Nrf2 signaling pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The flavonoid scutellarin (Scu) is a principal bioactive component of Erigeron breviscapus, a herb long utilized in the traditional medicine of the Miao and Yi peoples of China for the treatment of cardiovascular, inflammatory, and respiratory disorders. Despite its established use in ethnomedicine, the protective mechanisms of Scu in chronic obstructive pulmonary disease (COPD) remain poorly elucidated. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of Scu on COPD, with a specific focus on its role in regulating ferroptosis and elucidating the underlying molecular mechanisms. MATERIALS AND METHODS: An integrated strategy of computational and experimental approaches was employed. Network pharmacology and molecular docking identified Scu's core targets and pathways against COPD, which were subsequently verified in vitro in CSE-induced BEAS-2B cells and in vivo in a murine COPD model induced by CS exposure. RESULTS: Network pharmacology and molecular docking identified the PI3K/AKT pathway as the central mechanism and predicted high-affinity binding between Scu and core targets, including PIK3CA. Experimentally, Scu demonstrated potent anti-ferroptotic effects in vitro. In vivo, Scu ameliorated CS-induced lung function impairment and alveolar destruction, with suppressing ferroptosis in lung tissues. Pharmacological inhibition of either PI3K or Nrf2 validated the essential role of the PI3K/AKT/Nrf2 axis in mediating Scu's protection. CONCLUSION: Our study demonstrates that Scu alleviates CS-induced COPD by inhibiting ferroptosis, primarily through activation of the PI3K/AKT/Nrf2 pathway, providing a comprehensive pharmacological basis for Scu as a promising therapeutic candidate for COPD.