Wang Junlu, Lei Lingli, Wang Shasha, Sun Yuanyuan
State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China; First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China.
State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China; School of Clinical Medical Sciences, Clinical medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
Phytomedicine. 2025 Oct;146:157137. doi: 10.1016/j.phymed.2025.157137. Epub 2025 Aug 5.
Asiaticoside (AT), a triterpenoid derived from Centella asiatica, has long been recognized for its anti-inflammatory properties. Its potential to ameliorate atherosclerosis (AS), a chronic inflammatory disease, positions it as a promising therapeutic agent, although its underlying mechanisms remain to be fully elucidated.
This study aimed to evaluate the anti-atherosclerotic effects of AT and elucidate the molecular mechanisms underlying its therapeutic actions in AS.
The research included in vivo animal experiments, in vitro cellular studies, and target exploration and validation.
High-fat diet-induced ApoE mice were treated with AT or statins to assess AS progression, while ApoE mice fed a chow diet served as controls. Network pharmacology and RNA sequencing (RNA-Seq) of aortas identified dysregulated target genes and pathways. Oxidized low-density lipoprotein (Ox-LDL)-stimulated peritoneal macrophages were used for in vitro studies. Molecular docking, dynamics simulations, surface plasmon resonance (SPR) arrays, Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence were conducted to elucidate AT's anti-inflammatory mechanisms.
AT treatment significantly attenuated AS progression and enhanced plaque stability in the aortic roots of ApoE mice by reducing macrophage infiltration in plaques in vivo and suppressing inflammation in ox-LDL-stimulated macrophages in vitro. Integrated network pharmacology and RNA-Seq analyses identified Ras homolog family member F (RhoF) as a key target, with significantly elevated RhoF expression in AS plaques and macrophages, which was markedly reduced by AT treatment. Mechanistically, AT bound to RhoF, promoting its proteasome-mediated degradation, which further suppressed Nuclear Factor kappa-B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, thereby inhibiting inflammation.
AT mitigates AS progression and enhances plaque stability in ApoE mice by suppressing inflammation through RhoF proteasomal degradation and inhibition of NF-κB/MAPK signaling pathways, highlighting its potential as an anti-atherosclerotic therapeutic agent. These effects may offer advantages over current anti-inflammatory agents, such as tumor necrosis factor (TNF) inhibitors, by targeting protein stability to reduce plaque rupture risk. Its promising clinical translation value warrants further exploration.
积雪草苷（AT）是一种从积雪草中提取的三萜类化合物，长期以来因其抗炎特性而受到认可。尽管其潜在机制仍有待充分阐明，但它改善动脉粥样硬化（AS）这种慢性炎症性疾病的潜力使其成为一种有前景的治疗药物。
本研究旨在评估AT的抗动脉粥样硬化作用，并阐明其在AS治疗作用的分子机制。
该研究包括体内动物实验、体外细胞研究以及靶点探索与验证。
用高脂饮食诱导ApoE小鼠，用AT或他汀类药物治疗以评估AS进展，而喂食普通饮食的ApoE小鼠作为对照。对主动脉进行网络药理学和RNA测序（RNA-Seq）以确定失调的靶基因和通路。用氧化型低密度脂蛋白（Ox-LDL）刺激的腹腔巨噬细胞进行体外研究。进行分子对接、动力学模拟、表面等离子体共振（SPR）阵列、蛋白质印迹（WB）、免疫组织化学（IHC）和免疫荧光以阐明AT的抗炎机制。
AT治疗通过减少体内斑块中的巨噬细胞浸润和抑制体外Ox-LDL刺激的巨噬细胞中的炎症，显著减轻了ApoE小鼠主动脉根部的AS进展并增强了斑块稳定性。综合网络药理学和RNA-Seq分析确定Ras同源家族成员F（RhoF）为关键靶点，RhoF在AS斑块和巨噬细胞中的表达显著升高，而AT治疗可使其明显降低。机制上，AT与RhoF结合，促进其蛋白酶体介导的降解，进而抑制核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路，从而抑制炎症。
AT通过RhoF蛋白酶体降解和抑制NF-κB/MAPK信号通路抑制炎症，减轻ApoE小鼠的AS进展并增强斑块稳定性，突出了其作为抗动脉粥样硬化治疗药物的潜力。这些作用可能比目前的抗炎药物如肿瘤坏死因子（TNF）抑制剂更具优势，通过靶向蛋白质稳定性来降低斑块破裂风险。其有前景的临床转化价值值得进一步探索。
