Department of Endocrinology, Jining First People's Hospital, Jining 272000, China; Department of Clinical Medicine, Jining Medical University, Jining 272013, China; Cisen Pharmaceutical Co., Ltd, Jining 272000, China; School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Clinical Medical Laboratory Center, Jining First People's Hospital, Jining 272000, China.
Int J Biol Macromol. 2024 Nov;279(Pt 3):135209. doi: 10.1016/j.ijbiomac.2024.135209. Epub 2024 Sep 5.
This study aimed to evaluate the efficacy and therapeutic mechanism of parthenolide (PTL) in breast cancer (BC) through a comprehensive strategy integrating network pharmacology, single-cell RNA sequencing (scRNA-seq) and metabolomics. In network pharmacology, 70 therapeutic targets were identified, of which 16 core targets were filtered out through seven classical algorithms of Cytohubba plugin. Additionally, the hub module of PPI network was extracted using MCODE plugin. Molecular docking and molecular dynamics simulation showed a potent binding affinity between PTL and JNK, subsequently validated by MST and SPR assays. Further, Mendelian randomization analysis indicated that JNK was causally associated with BC. GO and KEGG enrichment analyses revealed that PTL counteracted BC via promoting ROS generation, inducing apoptosis and suppressing proliferation, which potentially involved the coordinated regulation of MAPK and FoxO1 pathways. Moreover, ssGSEA and scRNA-seq analysis suggested that PTL may act on T cell immune microenvironment of BC. Subsequently, these bioinformatics-based predictions were experimentally validated using in-vitro and in-vivo models. Finally, metabolome profiling unveiled that PTL remodeled the glycine, serine and threonine metabolism as well as biosynthesis of unsaturated fatty acids, and thereby contributed to BC inhibition. From molecular, immune and metabolic perspectives, this study not only provided a unique insight into the mechanistic details of PTL against BC, but also proposed a novel promising therapeutic strategy for BC.
本研究采用网络药理学、单细胞 RNA 测序（scRNA-seq）和代谢组学相结合的综合策略，旨在评估小白菊内酯（PTL）在乳腺癌（BC）中的疗效和治疗机制。在网络药理学中，鉴定出 70 个治疗靶点，通过 Cytohubba 插件的 7 种经典算法筛选出 16 个核心靶点。此外，使用 MCODE 插件提取 PPI 网络的枢纽模块。分子对接和分子动力学模拟显示 PTL 与 JNK 具有很强的结合亲和力，随后通过 MST 和 SPR 测定验证。进一步的孟德尔随机化分析表明 JNK 与 BC 存在因果关系。GO 和 KEGG 富集分析表明，PTL 通过促进 ROS 生成、诱导细胞凋亡和抑制增殖来对抗 BC，这可能涉及 MAPK 和 FoxO1 途径的协调调节。此外，ssGSEA 和 scRNA-seq 分析表明，PTL 可能作用于 BC 的 T 细胞免疫微环境。随后，使用体外和体内模型对这些基于生物信息学的预测进行了实验验证。最后，代谢组学分析揭示 PTL 重塑了甘氨酸、丝氨酸和苏氨酸代谢以及不饱和脂肪酸的生物合成，从而有助于抑制 BC。从分子、免疫和代谢的角度来看，本研究不仅提供了对 PTL 抗 BC 机制细节的独特见解，还为 BC 提出了一种新的有前途的治疗策略。
