Diosmetin (DSM), a newly discovered natural flavonoid, found in citrus plants and olive leaves, has been reported to inhibit the progression of cancer when used as a food supplement. This study aimed to investigate DSM's anti-hepatocellular carcinoma (HCC) properties and possible molecular mechanisms. Hep3B and HCCLM3 cells were selected to evaluate the anti-HCC properties of DSM in vitro. RNA sequencing (RNA-seq) was used to identify the possible molecular targets and pathways. Gas chromatography-mass spectrometry (GC-MS) was used to evaluate the effect of DSM treatment on the primary metabolites of HCCLM3 cells. Tumor xenograft was performed in nude mice to examine the anti-HCC properties of DSM in vivo. The results showed that DSM inhibited the proliferation and migration of HCC cells in vitro in a dose-dependent manner. RNA-seq identified 4459 differentially expressed genes (DEGs) that were highly enriched in the cell cycle pathway. In addition, DSM regulated cell growth by arresting the cell cycle in the G1 phase by decreasing the expression of BCL2, CDK1, and CCND1. Furthermore, metabolomics analysis revealed that DSM interfered with the lipid metabolism pathway of HCC cells by significantly inhibiting the synthesis of metabolites, such as acetic acid, decanoic acid, glycerol, and L-proline. Subcutaneous tumor formation experiments revealed that DSM significantly reduced the tumor volume and weight when compared to the control. Immunohistochemical analysis further revealed that DSM treatment significantly decreased the expression of the proliferative marker KI67. Our findings demonstrated that DSM exhibited antitumor effects on HCC cells by inhibiting cell proliferation via cell cycle arrest and interfering with lipid metabolism.

中文翻译：

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薯蓣素通过调控细胞周期和脂代谢途径抑制肝癌细胞生长增殖

Diosmetin (DSM) 是一种新发现的天然类黄酮，存在于柑橘类植物和橄榄叶中，据报道用作食品补充剂时可抑制癌症的进展。本研究旨在探讨帝斯曼的抗肝细胞癌 (HCC) 特性和可能的​​分子机制。选择 Hep3B 和 HCCLM3 细胞来评估 DSM的体外抗 HCC 特性。RNA测序（RNA-seq）用于识别可能的分子靶点和途径。气相色谱-质谱 (GC-MS) 用于评估 DSM 处理对 HCCLM3 细胞初级代谢物的影响。在裸鼠中进行肿瘤异种移植以检查体内DSM 的抗 HCC 特性. 结果表明，DSM在体外以剂量依赖性方式抑制HCC细胞的增殖和迁移。RNA-seq 鉴定了 4459 个差异表达基因 (DEG)，这些基因在细胞周期通路中高度富集。此外，DSM 通过降低 BCL2、CDK1 和 CCND1 的表达将细胞周期阻滞在 G1 期来调节细胞生长。此外，代谢组学分析表明，DSM 通过显着抑制乙酸、癸酸、甘油和L等代谢物的合成来干扰 HCC 细胞的脂质代谢途径。-脯氨酸。皮下肿瘤形成实验表明，与对照相比，DSM 显着减少了肿瘤体积和重量。免疫组织化学分析进一步显示，DSM 治疗显着降低了增殖标志物 KI67 的表达。我们的研究结果表明，DSM通过细胞周期停滞抑制细胞增殖和干扰脂质代谢，对 HCC 细胞具有抗肿瘤作用。