Chen Fuqing, Cai Yifan, Chen Changzhou, Zhou Jianyin
Department of Hepatobiliary Surgery, Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Front Oncol. 2025 Jun 24;15:1571537. doi: 10.3389/fonc.2025.1571537. eCollection 2025.
(FF), a widely used traditional Chinese medicine, possesses anti-inflammatory, antiviral, and anticancer properties. However, the precise anticancer mechanisms of FF against hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain poorly understood. This study therefore aims to investigate the therapeutic potential of FF in HBV-related HCC and elucidate its underlying mechanisms.
The active components of FF and their putative target proteins were identified through network pharmacology, and their interactions were further validated via molecular docking and molecular dynamics (MD) simulations. assays were performed to evaluate the effects of FF extract on the viability, proliferation, and apoptosis of HBV-related HCC (HepG2.2.15) cells, along with the underlying molecular mechanisms. studies were performed to investigate the inhibitory effects of FF extract on subcutaneous xenograft tumors in nude mice, quantify serum cytokine levels, and evaluate the expression of key target proteins by immunohistochemistry.
A total of 23 active components of FF and their 201 associated targets were identified using the TCMSP database, whereas 1,296 differentially expressed genes related to HBV-related HCC were retrieved from the GEO database. We identified 42 overlapping target genes between FF and HBV-related HCC. KEGG pathway analysis revealed the IL-17 signaling pathway as a pivotal pathway, with three core genes (c-Jun, ESR1, and MMP9) demonstrating prognostic significance in survival outcomes. Ten compounds were classified as high-quality candidates. Molecular docking studies demonstrated that Bicuculline exhibited the strongest binding affinity toward the core target genes, while MD simulations confirmed the stability of Bicuculline-JUN/ESR1/MMP9 complexes. experiments demonstrated that FF extract significantly inhibited the viability and proliferation of HepG2.2.15 cells, induced apoptosis, and exerted its effects via modulation of the IL-17/MAPK signaling pathway. Notably, adenovirus-mediated overexpression experiments showed that ESR1 enhanced FF's anti-HCC effects, whereas JUN and MMP9 partially counteracted them, confirming their roles as functional targets. studies further confirmed that FF suppressed tumor growth, reduced serum levels of ALT, AST, TNF-α, and IL-17B in mice, and modulated the expression of core target genes.
The therapeutic potential of FF in HBV-related HCC was demonstrated, with its mechanism likely involving the regulation of multiple components, targets, and pathways. These findings establish a solid scientific foundation for exploring FF as a therapeutic option for HBV-related HCC.
(FF)是一种广泛使用的中药，具有抗炎、抗病毒和抗癌特性。然而，FF抗乙型肝炎病毒(HBV)相关肝细胞癌(HCC)的确切抗癌机制仍知之甚少。因此，本研究旨在探讨FF在HBV相关HCC中的治疗潜力，并阐明其潜在机制。
通过网络药理学鉴定FF的活性成分及其潜在靶蛋白，并通过分子对接和分子动力学(MD)模拟进一步验证它们之间的相互作用。进行实验以评估FF提取物对HBV相关HCC(HepG2.2.15)细胞活力、增殖和凋亡的影响，以及潜在的分子机制。进行体内研究以调查FF提取物对裸鼠皮下异种移植瘤的抑制作用，量化血清细胞因子水平，并通过免疫组织化学评估关键靶蛋白的表达。
使用TCMSP数据库共鉴定出FF的23种活性成分及其201个相关靶点，而从GEO数据库中检索到1296个与HBV相关HCC相关的差异表达基因。我们在FF和HBV相关HCC之间鉴定出42个重叠的靶基因。KEGG通路分析显示IL-17信号通路是关键通路，三个核心基因(c-Jun、ESR1和MMP9)在生存结局中具有预后意义。十种化合物被归类为高质量候选物。分子对接研究表明荷包牡丹碱对核心靶基因表现出最强的结合亲和力，而MD模拟证实了荷包牡丹碱-JUN/ESR1/MMP9复合物的稳定性。体外实验表明，FF提取物显著抑制HepG2.2.15细胞的活力和增殖，诱导凋亡，并通过调节IL-17/MAPK信号通路发挥作用。值得注意的是，腺病毒介导的过表达实验表明，ESR1增强了FF的抗HCC作用，而JUN和MMP9部分抵消了这些作用，证实了它们作为功能靶点的作用。体内研究进一步证实，FF抑制小鼠肿瘤生长，降低血清ALT、AST、TNF-α和IL-17B水平，并调节核心靶基因的表达。
证实了FF在HBV相关HCC中的治疗潜力，其机制可能涉及对多种成分、靶点和通路的调节。这些发现为探索FF作为HBV相关HCC的治疗选择奠定了坚实的科学基础。
