Zhang Xin-Mei, Yang Tao, Zeng Ying-Xin, Yang Xin, Rao Hui-Ting, Hu Nan, Xia Guo-Dong
Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Health Management Center, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Medicine (Baltimore). 2025 Sep 12;104(37):e44628. doi: 10.1097/MD.0000000000044628.
Liver damage, ranging from mild hepatic impairment to severe liver failure, presents a significant global health burden with limited therapeutic options. Understanding the molecular underpinnings of liver damage and identifying actionable protein targets are crucial for advancing treatment strategies. We employed summary-data-based Mendelian randomization and colocalization analyses to identify plasma proteins associated with 6 liver biomarkers (aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyltransferase, total bilirubin, and direct bilirubin) by leveraging proteomic data from the deCODE cohort. Functional enrichment analyses were conducted to elucidate biological roles, and protein-protein interaction networks were constructed to explore their relationship with current drug targets for liver damage drug prediction and molecular docking studies were performed to evaluate therapeutic potential and drug-target interactions. In the summary-data-based Mendelian randomization analysis, while 21 to 106 proteins were found to be significant, only 30 were validated as potential drug targets through colocalization analysis (PP.H4 > 0.8). Enrichment analysis shows involvement in purine metabolism, nucleotide metabolism, and other pathways. Protein-protein interaction networks identified interactions with known liver damage pathways. Drug prediction highlighted potential compounds, including 7,8-benzoflavone, quercetin and tetradioxin, with strong binding affinities validated by molecular docking. This integrative study identified 30 proteins with strong evidence as potential therapeutic targets for liver damage. We provide novel insights into the molecular mechanisms of liver damage and actionable leads for drug development. Further functional and clinical validation is warranted to translate these findings into personalized therapeutic strategies.
肝损伤，从轻度肝功能损害到严重肝衰竭，是一个重大的全球健康负担，治疗选择有限。了解肝损伤的分子基础并确定可操作的蛋白质靶点对于推进治疗策略至关重要。我们利用来自deCODE队列的蛋白质组学数据，采用基于汇总数据的孟德尔随机化和共定位分析，以鉴定与6种肝脏生物标志物（天冬氨酸转氨酶、丙氨酸转氨酶、碱性磷酸酶、γ-谷氨酰转移酶、总胆红素和直接胆红素）相关的血浆蛋白。进行功能富集分析以阐明生物学作用，并构建蛋白质-蛋白质相互作用网络以探索它们与当前肝损伤药物靶点的关系，进行分子对接研究以评估治疗潜力和药物-靶点相互作用。在基于汇总数据的孟德尔随机化分析中，虽然发现21至106种蛋白质具有显著性，但通过共定位分析（PP.H4 > 0.8）仅30种被验证为潜在药物靶点。富集分析显示参与嘌呤代谢、核苷酸代谢和其他途径。蛋白质-蛋白质相互作用网络确定了与已知肝损伤途径的相互作用。药物预测突出了潜在化合物，包括7,8-苯并黄酮、槲皮素和四氯二苯二恶英，通过分子对接验证了其强结合亲和力。这项综合研究确定了30种有充分证据的蛋白质作为肝损伤的潜在治疗靶点。我们为肝损伤的分子机制提供了新见解以及药物开发的可操作线索。需要进一步的功能和临床验证，以将这些发现转化为个性化治疗策略。
