Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism

Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine’s regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine’s impact on HLP. Moreover, matrine’s potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, thermal proteome profiling analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine’s capacity to upregulate LDLR expression and highlights its potential in treating HLP. These findings offer insights into matrine’s mechanism of action and open new avenues for drug research and lipid metabolism regulation.高脂血症（Hyperlipidemia, HLP）是一种高发的全身性代谢紊乱，以脂质代谢失衡为典型特征。他汀类药物（statin drugs）长期以来是血脂管理的首选方案，但因临床不耐受问题，促使学界探寻新型替代治疗手段。苦参碱（matrine）是从中药苦参（Kushen）中提取的天然活性化合物，具备抗炎与降脂双重活性。然而，苦参碱调控脂质代谢的具体分子机制至今尚未完全阐明。本研究围绕苦参碱调控脂质代谢的分子机制展开探究。通过定量蛋白质组学（quantitative proteomics）技术分析，我们发现苦参碱可上调HepG2与A549细胞内低密度脂蛋白受体（LDL receptor, LDLR）的表达水平；后续功能实验进一步验证了其可显著增强细胞对低密度脂蛋白的摄取能力。值得注意的是，在高脂血症仓鼠模型中，苦参碱可有效降低血脂水平且未对动物体重产生显著影响，这一结果证实LDLR是苦参碱发挥HLP调控作用的关键靶点。此外，苦参碱对肿瘤细胞低密度脂蛋白摄取的潜在抑制效应，提示其在癌症研究领域具备更广泛的应用潜力。同时，热蛋白质组图谱分析（thermal proteome profiling）鉴定出了一批可与苦参碱发生特异性相互作用的脂质代谢相关蛋白。综上，本研究揭示了苦参碱可通过上调LDLR表达发挥降脂作用，并凸显了其在高脂血症治疗中的应用前景。上述研究成果为阐明苦参碱的作用机制提供了全新视角，同时为药物研发与脂质代谢调控开辟了新的研究方向。