Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China.
Beijing University of Chinese Medicine, Beijing, China.
Ann Med. 2024 Dec;56(1):2404550. doi: 10.1080/07853890.2024.2404550. Epub 2024 Sep 20.
Hepatocellular carcinoma (HCC) remains a significant global medical challenge. Formononetin, an isoflavone derived from , has been shown to have various regulatory effects on HCC. However, the exact molecular mechanism by which formononetin acts against HCC is still unclear.
To elucidate the molecular mechanism of formononetin in treating HCC.
The potential targets of formononetin were retrieved from Swisstargets and SEA databases, while targets associated with HCC were sourced from GeneCards, NCBI and DisGeNET databases. The overlapping targets were visualized using protein-protein interaction (PPI) network analysis via String database, and subsequently subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking was employed to confirm the interaction between formononetin and key targets. Ultimately, the effectiveness of formononetin on HCC and the signalling pathway with the highest enrichment were confirmed in the HCC tumour-bearing mice. Histopathological changes in tumour tissues were observed using haematoxylin and eosin (HE) staining, while apoptosis of tumour cells in mice was assessed through TdT-mediated dUTP nick end labelling (TUNEL) and immunofluorescence staining. The most enriched signalling pathway was verified using Western blotting and immunohistochemical (IHC) staining.
One hundred and ninety-three potential targets related to formononetin, 6980 targets associated with HCC and 156 overlapping targets were obtained from the online public databases. Molecular docking studies demonstrated formononetin's robust interaction with core targets. KEGG enrichment analysis identified 111 signalling pathways, including PI3K/AKT and apoptosis signalling pathways. experiments demonstrated that formononetin significantly promoted apoptosis of tumour cell in mice, as confirmed by HE, TUNEL and immunofluorescence staining ( < .05). Formononetin was found to decrease the phosphorylation levels of PI3K and AKT, reduce the expression of Bcl-2, and increase the expression of cleaved-Caspase-3 and Bax ( < .05).
Formononetin demonstrates dose-dependent regulatory effects on multiple targets, biological processes and signalling pathways in HCC. The compound can mitigate HCC by enhancing PI3K/AKT-mediated apoptosis of tumour cells.
肝细胞癌（HCC）仍然是一个重大的全球医学挑战。芒柄花素是一种来源于大豆的异黄酮，已被证明对 HCC 具有多种调节作用。然而，芒柄花素作用于 HCC 的确切分子机制尚不清楚。
阐明芒柄花素治疗 HCC 的分子机制。
从 Swisstargets 和 SEA 数据库中检索芒柄花素的潜在靶点，从 GeneCards、NCBI 和 DisGeNET 数据库中检索与 HCC 相关的靶点。使用 String 数据库中的蛋白质-蛋白质相互作用（PPI）网络分析可视化重叠靶点，然后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。采用分子对接技术验证芒柄花素与关键靶点的相互作用。最终，在 HCC 荷瘤小鼠中验证芒柄花素对 HCC 的有效性和富集程度最高的信号通路。采用苏木精和伊红（HE）染色观察肿瘤组织的组织病理学变化，通过末端转移酶介导的 dUTP 缺口末端标记（TUNEL）和免疫荧光染色评估肿瘤细胞的凋亡。采用 Western blot 和免疫组化（IHC）染色验证富集程度最高的信号通路。
从在线公共数据库中获得了 193 个与芒柄花素相关的潜在靶点、6980 个与 HCC 相关的靶点和 156 个重叠靶点。分子对接研究表明芒柄花素与核心靶点具有很强的相互作用。KEGG 富集分析鉴定了 111 个信号通路，包括 PI3K/AKT 和细胞凋亡信号通路。实验表明，芒柄花素显著促进了小鼠肿瘤细胞的凋亡，HE、TUNEL 和免疫荧光染色证实了这一点（<0.05）。芒柄花素降低了 PI3K 和 AKT 的磷酸化水平，降低了 Bcl-2 的表达，增加了 cleaved-Caspase-3 和 Bax 的表达（<0.05）。
芒柄花素对 HCC 的多个靶点、生物过程和信号通路具有剂量依赖性的调节作用。该化合物可通过增强 PI3K/AKT 介导的肿瘤细胞凋亡来减轻 HCC。
