Liang Keke, Ta Yanlin, Xu Liang, Ma Shuhe, Wang Renjie, Xiao Chenrong, Gao Yue, Li Maoxing
College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730013, China.
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Nutrients. 2025 Jul 23;17(15):2406. doi: 10.3390/nu17152406.
, a traditional Chinese medicine, is renowned for its pharmacological effects in promoting blood circulation, resolving blood stasis, regulating menstruation, detoxification, and alleviating mental disturbances. Trans-crocetin, its principal bioactive component, exhibits significant anti-hypoxic activity. The clinical development and therapeutic efficacy of trans-crocetin are limited by its instability, poor solubility, and low bioavailability. Conversion of trans-crocetin into trans-sodium crocetinate (TSC) enhances its solubility, stability, and bioavailability, thereby amplifying its anti-hypoxic potential.
This study integrates network pharmacology with in vivo and in vitro validation to elucidate the molecular targets and mechanisms underlying TSC's therapeutic effects against high-altitude acute lung injury (HALI), aiming to identify novel treatment strategies.
TSC effectively reversed hypoxia-induced biochemical abnormalities, ameliorated lung histopathological damage, and suppressed systemic inflammation and oxidative stress in HALI rats. In vitro, TSC mitigated CoCl-induced hypoxia injury in human pulmonary microvascular endothelial cells (HPMECs) by reducing inflammatory cytokines, oxidative stress, and ROS accumulation while restoring mitochondrial membrane potential. Network pharmacology and pathway analysis revealed that TSC primarily targets the EGFR/PI3K/AKT/NF-κB signaling axis. Molecular docking and dynamics simulations demonstrated stable binding interactions between TSC and key components of this pathway. ELISA and RT-qPCR confirmed that TSC significantly downregulated the expression of EGFR, PI3K, AKT, NF-κB, and their associated mRNAs.
TSC alleviates high-altitude hypoxia-induced lung injury by inhibiting the EGFR/PI3K/AKT/NF-κB signaling pathway, thereby attenuating inflammatory responses, oxidative stress, and restoring mitochondrial function. These findings highlight TSC as a promising therapeutic agent for HALI.
中药藏红花以其促进血液循环、活血化瘀、调经、解毒和安神等药理作用而闻名。其主要生物活性成分反式西红花酸具有显著的抗缺氧活性。反式西红花酸的临床开发和治疗效果受到其不稳定性、低溶解度和低生物利用度的限制。将反式西红花酸转化为反式西红花酸钠（TSC）可提高其溶解度、稳定性和生物利用度，从而增强其抗缺氧潜力。
本研究将网络药理学与体内外验证相结合，以阐明TSC治疗高原急性肺损伤（HALI）的分子靶点和机制，旨在确定新的治疗策略。
TSC有效逆转了缺氧诱导的生化异常，改善了肺组织病理学损伤，并抑制了HALI大鼠的全身炎症和氧化应激。在体外，TSC通过减少炎症细胞因子、氧化应激和ROS积累，同时恢复线粒体膜电位，减轻了CoCl诱导的人肺微血管内皮细胞（HPMECs）的缺氧损伤。网络药理学和通路分析表明，TSC主要靶向EGFR/PI3K/AKT/NF-κB信号轴。分子对接和动力学模拟证明了TSC与该通路关键成分之间的稳定结合相互作用。ELISA和RT-qPCR证实，TSC显著下调了EGFR、PI3K、AKT、NF-κB及其相关mRNA的表达。
TSC通过抑制EGFR/PI3K/AKT/NF-κB信号通路减轻高原缺氧诱导的肺损伤，从而减轻炎症反应、氧化应激并恢复线粒体功能。这些发现突出了TSC作为HALI一种有前景的治疗药物的地位。
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