Liu Xuanhe, Zhang Dan, Xie Yuting, Wang Mengdan, Chen Xiaochun, Yu Weijie, Ma Yuming, Zeng Jia, Long Qixuan, Huang Guangrui, Geng Jie, Xu Anlong
School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China.
School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100029, China.
Pharmaceuticals (Basel). 2025 May 25;18(6):789. doi: 10.3390/ph18060789.
Acute kidney injury (AKI), characterized by high morbidity and mortality, is primarily caused by renal ischemia-reperfusion injury (RIRI). Ferroptosis plays a key role in RIRI, yet its underlying mechanisms remain unclear. The drug pair of Astragali Radix-Ligustri Lucidi Fructus (DAL) shows promise in renal diseases, but its protective effects against RIRI and associated molecular pathways via ferroptosis inhibition are unknown. This study aimed to investigate DAL's therapeutic effects on RIRI and its mechanisms. : A mouse model of bilateral renal ischemia-reperfusion was established. Renal function (serum creatinine, Scr; blood urea nitrogen, BUN), inflammatory cytokines (TNF-α, IFN-γ, IL-6), ferroptosis markers (GPX4, MDA, GSH, tissue iron), and pathological damage were evaluated. Transcriptomic sequencing and electron microscopy analyzed gene pathways and mitochondrial structure. In HK-2 cells, oxygen-glucose deprivation/reoxygenation (OGD/R) and RSL3-induced ferroptosis models were used to assess DAL-containing serum effects via cell viability, GPX4 expression, and mitochondrial morphology. LC-MS analyzed DAL's chemical components, and network pharmacology predicted ferroptosis-related targets. : DAL significantly reduced Scr/BUN levels, alleviated tubular injury, fibrosis, and apoptosis, and downregulated inflammatory cytokines and damage markers. It inhibited ferroptosis by upregulating GPX4, decreasing MDA/tissue iron, and increasing GSH. Transcriptomics revealed enrichment in lipid metabolism pathways. DAL restored the mitochondrial cristae structure; DAL-containing serum improved cell viability, blocked RSL3-induced GPX4 downregulation, and mitigated mitochondrial dysfunction. Network pharmacology identified DAL's potential active components and targets. Molecular docking validated binding affinity and interaction patterns of active components with targets. : DAL protects against RIRI by upregulating GPX4, preserving the mitochondrial structure, and inhibiting ferroptosis, highlighting its therapeutic potential for AKI prevention and treatment.
急性肾损伤（AKI）发病率和死亡率高，主要由肾缺血再灌注损伤（RIRI）引起。铁死亡在RIRI中起关键作用，但其潜在机制尚不清楚。黄芪-女贞子药对（DAL）在肾脏疾病中显示出前景，但其通过抑制铁死亡对RIRI的保护作用及相关分子途径尚不清楚。本研究旨在探讨DAL对RIRI的治疗作用及其机制。：建立双侧肾缺血再灌注小鼠模型。评估肾功能（血清肌酐，Scr；血尿素氮，BUN）、炎性细胞因子（TNF-α、IFN-γ、IL-6）、铁死亡标志物（GPX4、丙二醛，MDA、谷胱甘肽，GSH、组织铁）和病理损伤。转录组测序和电子显微镜分析基因途径和线粒体结构。在HK-2细胞中，使用氧糖剥夺/复氧（OGD/R）和RSL3诱导的铁死亡模型，通过细胞活力、GPX4表达和线粒体形态评估含DAL血清的作用。液相色谱-质谱联用（LC-MS）分析DAL的化学成分，网络药理学预测铁死亡相关靶点。：DAL显著降低Scr/BUN水平，减轻肾小管损伤、纤维化和凋亡，并下调炎性细胞因子和损伤标志物。它通过上调GPX4、降低MDA/组织铁和增加GSH来抑制铁死亡。转录组学显示脂质代谢途径富集。DAL恢复线粒体嵴结构；含DAL血清提高细胞活力，阻断RSL3诱导的GPX4下调，并减轻线粒体功能障碍。网络药理学确定了DAL的潜在活性成分和靶点。分子对接验证了活性成分与靶点的结合亲和力和相互作用模式。：DAL通过上调GPX4、维持线粒体结构和抑制铁死亡来预防RIRI，突出了其在AKI防治中的治疗潜力。
