Sun Peng, Song Jiahui, Liu Yang, Li Xiujing, Zhang Yiming, Zhou Yuxing, Gong Wei
Science and Technology Center Ningxia Medical University Yinchuan China.
Ningxia Hui Autonomous Region Institute of Medical Sciences Yinchuan China.
Food Sci Nutr. 2025 May 26;13(6):e70256. doi: 10.1002/fsn3.70256. eCollection 2025 Jun.
Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are prevalent metabolic disorders that frequently coexist, yet their shared molecular mechanisms remain poorly understood, and current therapies often yield suboptimal outcomes. L. (, LF), a traditional medicinal herb, has demonstrated clinical efficacy in treating both conditions, but its mechanism of action in comorbidity management remains unclear. Active LF compounds were identified via the TCMSP database, with potential targets predicted using Swiss Target Prediction and PharmMapper. Disease-associated proteins for NAFLD and DM were curated from OMIM, GeneCards, DisGeNET, UniProt, DrugBank, and TTD. A protein-protein interaction (PPI) network was constructed from these targets, and GO and KEGG pathway analyses were performed using the DAVID platform. Key targets were further refined through network module analysis via Metascape. Drug-likeness of bioactive compounds was assessed using SwissADME and ADMETlab 2.0. Molecular docking and dynamics simulations validated interactions between core targets and LF compounds. Mendelian randomization (MR) analysis tested causal relationships between core genes and disease phenotypes. We identified 58 shared therapeutic targets for NAFLD-DM comorbidity, including HSP90AA1, ESR1, MMP9, EGFR, AKT1, and CASP3. GO analysis implicated LF in blood pressure regulation and glucose-stimulated insulin secretion. KEGG pathways highlighted modulation of MAPK, PI3K-Akt, FoxO, and mTOR signaling. 24-methylenelanost-8-enol and cryptoxanthin monoepoxide emerged as core bioactive compounds with favorable drug-likeness. Molecular docking confirmed strong binding of 24-methylenelanost-8-enol to HSP90AA1 and cryptoxanthin monoepoxide to MMP9, further supported by dynamics simulations. MR analysis revealed a significant causal role for CASP3 in both NAFLD and DM, aligning with network pharmacology predictions. LF's therapeutic effects on NAFLD-DM comorbidity likely arise from terpenoid and cryptoxanthin mediated modulation of apoptosis and inflammation pathway. This study identifies shared molecular networks, proposes candidate mechanisms for LF's efficacy, and provides a framework for targeting multifactorial metabolic diseases.
非酒精性脂肪性肝病（NAFLD）和糖尿病（DM）是常见的代谢紊乱疾病，常同时存在，但其共同的分子机制仍知之甚少，目前的治疗效果往往不尽人意。传统草药光叶楮（L.，LF）已显示出对这两种疾病的临床治疗效果，但其在合并症管理中的作用机制仍不清楚。通过中药系统药理学数据库（TCMSP）鉴定了光叶楮的活性化合物，并使用瑞士靶点预测（Swiss Target Prediction）和药靶预测（PharmMapper）预测潜在靶点。从在线人类孟德尔遗传数据库（OMIM）、基因卡片（GeneCards）、疾病基因数据库（DisGeNET）、通用蛋白质数据库（UniProt）、药物银行（DrugBank）和治疗靶点数据库（TTD）中整理出与NAFLD和DM相关的蛋白质。基于这些靶点构建了蛋白质-蛋白质相互作用（PPI）网络，并使用DAVID平台进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析。通过Metascape进行网络模块分析进一步优化关键靶点。使用瑞士药物相似性评估工具（SwissADME）和ADMETlab-2.0评估生物活性化合物的药物相似性。分子对接和动力学模拟验证了核心靶点与光叶楮化合物之间的相互作用。孟德尔随机化（MR）分析测试核心基因与疾病表型之间的因果关系。我们确定了58个NAFLD-DM合并症的共同治疗靶点，包括热休克蛋白90α家族成员1（HSP90AA1）、雌激素受体1（ESR1）、基质金属蛋白酶9（MMP9）、表皮生长因子受体（EGFR）、蛋白激酶B（AKT1）和半胱天冬酶3（CASP3）。GO分析表明光叶楮参与血压调节和葡萄糖刺激的胰岛素分泌。KEGG通路突出了丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）、叉头框蛋白O（FoxO）和哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的调节。24-亚甲基环阿尔廷醇和隐黄质单环氧化物成为具有良好药物相似性的核心生物活性化合物。分子对接证实24-亚甲基环阿尔廷醇与HSP90AA1以及隐黄质单环氧化物与MMP9有强烈结合，动力学模拟进一步支持了这一结果。MR分析揭示了CASP3在NAFLD和DM中均具有显著的因果作用，这与网络药理学预测一致。光叶楮对NAFLD-DM合并症的治疗作用可能源于萜类化合物和隐黄质介导的细胞凋亡和炎症通路调节。本研究确定了共同的分子网络，提出了光叶楮疗效的候选机制，并为靶向多因素代谢疾病提供了框架。
