Li Hangting, Xu Ke, Mao Wenhao, Yu Bojian, Liu Zhongliang, Huang Fangfang, Yang Zuisu
School of Food and Pharmacy, Zhejiang Ocean University, Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, Zhoushan 316022, China.
School of Marine Engineering Equipment, Zhejiang Ocean University, Zhoushan 316022, China.
Int Immunopharmacol. 2025 Apr 24;153:114430. doi: 10.1016/j.intimp.2025.114430. Epub 2025 Mar 17.
The clinical use of cisplatin as a chemotherapeutic agent is limited owing to its nephrotoxicity. Oxidative stress and ferroptosis are responsible for cisplatin-induced renal injury.
The protective effects of morroniside against cisplatin-induced renal injury were evaluated and its underlying molecular mechanisms were elucidated.
An animal model of cisplatin-induced renal injury was established using male C57BL/6 mice. Renal function was assessed by measuring serum creatinine (CRE), uric acid (UA), and blood urea nitrogen (BUN) levels. Antioxidant enzyme activity and pro-inflammatory cytokine levels were determined, and histological studies of renal and colon tissues were performed. Western blotting and immunohistochemical analysis were performed to determine the expression of ferroptosis-related proteins and nuclear factor erythroid 2-related factor (Nrf)2 signaling pathway. Gut microbiota were analyzed using 16S rRNA sequencing. Cisplatin- or erastin-induced renal tubular epithelial cell (HK-2 cells) models were established. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were measured. The expression of Nrf2, heme oxygenase 1 (HO-1), tumor protein 53 (p53) and glutathione peroxidase (GPX)4 proteins were determined using immunofluorescence.
Morroniside significantly ameliorated cisplatin-induced renal dysfunction, as evidenced by decreased serum CRE, UA, and BUN levels. It reduced pro-inflammatory cytokine levels, enhanced antioxidant enzyme levels, and improved renal and colon histology. Morroniside corrected gut dysbiosis, reduced ROS levels, increased mitochondrial membrane potential, and decreased HK-2 cell apoptosis, alleviating cisplatin- or erastin-induced oxidative stress and ferroptosis.
Morroniside mitigated cisplatin-induced renal injury by inhibiting ferroptosis through the GPX4/p53 pathway, reducing oxidative stress via Nrf2/HO-1 axis, and improving gut microbiota dysbiosis, indicating its potential in mitigating cisplatin-induced renal injury.
顺铂作为一种化疗药物，因其肾毒性，临床应用受到限制。氧化应激和铁死亡是顺铂诱导肾损伤的原因。
评估莫诺苷对顺铂诱导肾损伤的保护作用，并阐明其潜在的分子机制。
使用雄性C57BL/6小鼠建立顺铂诱导肾损伤的动物模型。通过测量血清肌酐（CRE）、尿酸（UA）和血尿素氮（BUN）水平评估肾功能。测定抗氧化酶活性和促炎细胞因子水平，并对肾和结肠组织进行组织学研究。进行蛋白质免疫印迹和免疫组织化学分析，以确定铁死亡相关蛋白和核因子红细胞2相关因子（Nrf）2信号通路的表达。使用16S rRNA测序分析肠道微生物群。建立顺铂或埃拉司亭诱导的肾小管上皮细胞（HK-2细胞）模型。测量细胞内活性氧（ROS）水平和线粒体膜电位。使用免疫荧光法测定Nrf2、血红素加氧酶1（HO-1）、肿瘤蛋白53（p53）和谷胱甘肽过氧化物酶（GPX）4蛋白的表达。
莫诺苷显著改善了顺铂诱导的肾功能障碍，血清CRE、UA和BUN水平降低证明了这一点。它降低了促炎细胞因子水平，提高了抗氧化酶水平，并改善了肾和结肠组织学。莫诺苷纠正了肠道菌群失调，降低了ROS水平，增加了线粒体膜电位，并减少了HK-2细胞凋亡，减轻了顺铂或埃拉司亭诱导的氧化应激和铁死亡。
莫诺苷通过GPX4/p53途径抑制铁死亡、通过Nrf2/HO-1轴降低氧化应激并改善肠道微生物群失调，减轻了顺铂诱导的肾损伤，表明其在减轻顺铂诱导肾损伤方面的潜力。
