Ni Jiajie, Huang Liru, Tian Yifan, Zhao Changxin, Zhou Ziyi, Shen Feihai, Huang Zhiying
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Pharmaceuticals (Basel). 2025 Jul 21;18(7):1078. doi: 10.3390/ph18071078.
: (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. : HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. : Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis.
使君子（FMT）是一种用于治疗蛔虫病的中药；然而，其报道的肝毒性限制了其应用。川楝素（TSN）作为主要活性成分，被认为是导致使君子诱导肝毒性的主要有毒成分，但其潜在机制仍不清楚。用TSN处理HepG2细胞，并使用蛋白质免疫印迹法和qPCR分析相关基因转录和蛋白质表达。测量脂质过氧化和铁死亡标志物。给Balb/c和C57BL/6小鼠给予不同剂量的TSN，并用血清生物化学和组织病理学评估其肝功能。进行网络药理学和氧化脂质组学以鉴定关键靶点和代谢物。TSN在体外和体内均引发铁死亡，伴随着5-脂氧合酶（ALOX5）及其下游代谢物表达的升高。ALOX5水平调节肝细胞对TSN诱导的铁死亡损伤的敏感性。在体内敲低ALOX5可减轻TSN诱导的肝损伤和铁死亡。我们的研究表明，TSN通过促进ALOX5介导的脂质过氧化诱导肝毒性，从而使细胞对铁死亡敏感。
