Prophylactic isoimperatorin protects against LPS-ALI via mTOR-dependent control of inflammation, oxidative stress and ferroptosis markers

作者：Jiecheng Zhang, Ziyi Zhang, Tianqi Cui, Xi Tang, Jiayu Li, Chenlu Ma, Tingting Chen, Xiaoqin Wu, Min Qiu, Danna Wang, Zhiyi Cui, Haojie Zuo, Li Xu, Weiru Liu, Wenjun Zhao, Liang Yin, Zhiqun Xing, Yinliang Zhang, Jia Ke, Xiaoying Yang, Qīng Wáng · 发表于：Journal of Ethnopharmacology · 年份：2025 · DOI：10.1016/j.jep.2025.120998 · 被引用次数：3 · 研究领域：Ferroptosis and cancer prognosis、Inflammasome and immune disorders、PI3K/AKT/mTOR signaling in cancer

ETHNOPHARMACOLOGICAL RELEVANCE: Isoimperatorin (ISO) is a furanocoumarin from Angelica dahurica (Bai Zhi), traditionally used in TCM for respiratory complaints such as allergic asthma, sinusitis, and cough, with reported anti-inflammatory and antioxidant activities. Its role in acute lung injury (ALI), however, remains insufficiently defined. AIM OF THE STUDY: To elucidate ISO's protective efficacy and underlying mechanisms against LPS. MATERIALS AND METHODS: An LPS-induced ALI mouse model and LPS-stimulated RAW264.7 cells were used. ISO was administered prophylactically once daily for seven days before LPS challenge. Lung histopathology, cytokines (serum, BALF, lung tissue), and oxidative stress indices were assessed. Signaling pathways were examined by Western blot, immunohistochemistry, and qPCR. Target nomination employed RNA-seq, network pharmacology, molecular docking, and molecular dynamics; target engagement was evaluated by CETSA. Mechanistic dependence was tested by mTOR siRNA in vitro and pharmacologic activation with MHY1485 in vitro and in vivo. RESULTS: Prophylactic ISO protected against LPS-induced lung injury, attenuating histologic edema, lowering pro-inflammatory cytokines and oxidative markers, and enhancing antioxidant defenses. ISO suppressed TLR4/MyD88/NF-κB signaling, limited TXNIP/NLRP3 inflammasome activation, activated Keap1/Nrf2-associated antioxidant responses, and restored GPX4 together with iron-handling markers such as PCBP1 and SLC40A1, consist...