Luo Mei, Wang Yuelian, Liu Xiaodong, Liu Lin, Zhu Li, Chen Guo, Ye Qing, He Chengshi, Xiao Xujue, Li Jike
Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu 610061, China.
Center for Precision and Translational Medicine, Chengdu Public Health Clinical Center, Chengdu 610061, China.
Am J Chin Med. 2025;53(5):1573-1589. doi: 10.1142/S0192415X25500600. Epub 2025 Jul 7.
Among the spectrum of digestive system cancers, hepatocellular carcinoma (HCC) poses a particularly formidable challenge due to its poor prognosis. Geniposide, an iridoid glucoside extracted from the fruit of Ellis, exhibits a diverse array of biological activities. The goal of this study is to delineate the specific roles and underlying mechanisms of geniposide on the progression of HCC. Cell viability, apoptosis and migration of Huh7 and HepG2 cells were, respectively, assessed via CCK-8, flow cytometry and trans-well assays. The level of reactive oxygen species (ROS) was assessed with a dihydroethidium (DHE) probe. The measurement of mitochondrial membrane potential (MMP) was conducted using JC-1 staining. Ferroptosis-related markers were evaluated by Western Blot assay. Transcriptome sequencing was performed in HCC cells both treated and untreated with geniposide. experiments were applied with the subcutaneous xenograft tumor model. experiments revealed that geniposide exerted a concentration-dependent suppression on cell viability and migration, concurrently eliciting apoptosis in HCC cells. Ferroptosis was identified as the main form of geniposide-induced cell death in HCC. Geniposide promoted the iron ions levels, ROS accumulation, and the expression of ferroptosis markers, which were partially reversed by the addition of deferoxamine (DFO, ferroptosis inhibitor). Intersection analysis was applied between upregulated genes of HCC cells and ferroptosis-related genes. DUOX1 was proven to be involved in geniposide-mediated roles in HCC. experiments further clarified the suppressive effects of geniposide on tumors. Geniposide treatment increased intracellular iron ions and induced ferroptosis in HCC. Geniposide attenuated tumor progression and oxidative stress via DUOX1-mediated ferroptosis.
在消化系统癌症谱系中，肝细胞癌（HCC）因其预后较差而构成了特别严峻的挑战。栀子苷是从栀子果实中提取的一种环烯醚萜苷，具有多种生物活性。本研究的目的是阐明栀子苷在HCC进展中的具体作用和潜在机制。分别通过CCK-8、流式细胞术和Transwell实验评估Huh7和HepG2细胞的活力、凋亡和迁移情况。用二氢乙锭（DHE）探针评估活性氧（ROS）水平。使用JC-1染色进行线粒体膜电位（MMP）的测定。通过蛋白质免疫印迹法评估铁死亡相关标志物。对经栀子苷处理和未处理的HCC细胞进行转录组测序。实验应用于皮下异种移植肿瘤模型。实验表明，栀子苷对细胞活力和迁移具有浓度依赖性抑制作用，同时诱导HCC细胞凋亡。铁死亡被确定为栀子苷诱导HCC细胞死亡的主要形式。栀子苷促进铁离子水平、ROS积累以及铁死亡标志物的表达，添加去铁胺（DFO，铁死亡抑制剂）可部分逆转这些作用。对HCC细胞上调基因与铁死亡相关基因进行交集分析。证实DUOX1参与了栀子苷在HCC中的介导作用。实验进一步阐明了栀子苷对肿瘤的抑制作用。栀子苷处理增加了HCC细胞内铁离子水平并诱导铁死亡。栀子苷通过DUOX1介导的铁死亡减轻肿瘤进展和氧化应激。
