Coptisine mitigates acute lung injury by alleviating ferroptosis through the PI3K/AKT/Nrf2 pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch is a traditional Chinese medicinal herb renowned for its anti-inflammatory effects. Coptisine (COP), its primary active constituent, exhibits multiple pharmacological properties, yet its therapeutic impact on acute lung injury (ALI) warrants further investigation. AIM OF THE STUDY: The research aimed to elucidate COP's protective effects against ALI and its underlying molecular mechanisms. MATERIALS AND METHODS: Network pharmacology and RNA-seq analyses identified COP-associated targets and pathways. An LPS-induced ALI mouse model was established, with therapeutic effects assessed via histopathology, immunofluorescence, and Western blot. TBHP-stimulated MLE-12 cells and molecular docking were used for mechanistic validation. RESULTS: Transcriptomic profiling identified the PI3K/AKT pathway as the central mediator of COP's anti-ALI effects, with ferroptosis suppression as a key mechanism. COP administration significantly attenuated LPS-induced pulmonary edema, inflammatory infiltration, and pro-inflammatory cytokine levels in bronchoalveolar lavage fluid. Mechanistically, COP restored redox homeostasis by elevating glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) levels while reducing Feaccumulation and lipid peroxidation. Furthermore, COP reversed the downregulation of ferroptosis-associated proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4). The therapeutic efficacy of COP was abolished by ML385, a selective Nrf2 inhibitor, confirming Nrf2-dependent activity. CONCLUSION: This study demonstrates that COP ameliorates ALI by activating the PI3K/AKT/Nrf2 pathway, thereby attenuating inflammatory cascades and ferroptosis. These findings establish COP as a promising pre-clinical candidate for ALI management and underscore the therapeutic relevance of targeting ferroptosis in inflammatory lung diseases.