Yan Xiangying, Liu Yudong, Li Congchong, Mao Xia, Xu Tengteng, Hu Zhixing, Zhang Chu, Lin Na, Lin Ya, Zhang Yanqiong
College of Pharmacy, Fujian University of Traditional Chinese Medicine, No. 1, Qiuyang Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
Cancer Cell Int. 2023 Jun 6;23(1):109. doi: 10.1186/s12935-023-02946-2.
Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation.
A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the "disease-related gene-drug effective target" interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro.
PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats.
Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.
肝纤维化向癌变的恶性转化可能是肝细胞癌（HCC）的一个治疗靶点。本研究旨在评估片仔癀（PZH）的抗癌疗效，并通过整合转录调控网络分析和实验验证来探究其潜在机制。
建立二乙基亚硝胺（DEN）诱导的大鼠肝癌模型，用于评估PZH的抗癌疗效。在检测转录组谱后，构建“疾病相关基因-药物有效靶点”相互作用网络，并在体外鉴定和验证PZH针对肝纤维化向HCC恶性转化的候选靶点。
PZH有效减轻了肝纤维化和肝硬化的病理变化，并抑制了DEN诱导的HCC大鼠的肿瘤形成和生长。此外，给予PZH显著降低了各种肝功能相关血清学指标的水平。机制上，铁死亡相关的SLC7A11-GSH-GPX4轴可能是PZH针对肝纤维化向HCC恶性转化的潜在靶点之一。特别是，SLC7A11高表达可能与HCC患者的不良预后相关。实验表明，给予PZH显著增加了三价铁和二价铁离子，抑制了SLC7A11和GPX4蛋白的表达水平，并降低了DEN诱导的HCC大鼠肝组织中的谷胱甘肽/氧化型谷胱甘肽比值。
我们的数据提供了证据表明，PZH可能通过抑制SLC7A11-GSH-GPX4轴促进肿瘤细胞铁死亡，从而有效改善肝纤维化微环境并预防HCC的发生，这意味着PZH可能是早期预防和治疗HCC的潜在候选药物。
