基于多组学探讨肾阳虚证绝经后骨质疏松症的生物标志物及潜在治疗中药
作者：李远志1，时宗庭2，迟敬轩1，李志文1，黄江海3，方志远3，童昊坤1
单位：1.北京中医药大学第二临床医学院，北京 100078； 2.北京中医药大学第三临床医学院，北京 100029； 3.北京中医药大学东方医院，北京 100078
引用：引用：李远志，时宗庭，迟敬轩，李志文，黄江海，方志远，童昊坤.基于多组学探讨肾阳虚证绝经后骨质疏松症的生物标志物及潜在治疗中药[J].中医药导报,2025,31(6):115-123.
DOI：10.13862/j.cn43-1446/r.2025.06.020
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摘要：目的：通过多组学探索肾阳虚证绝经后骨质疏松症（PMOP）的生物标志物及发病机制，并寻找其潜在的中药治疗策略。方法：通过高通量基因表达数据库（GEO）检索肾阳虚证PMOP相关芯片，利用R语言limma包分析得到肾阳虚证PMOP特有差异基因。利用Cytoscape3.10.2中MCODE插件分析肾阳虚证PMOP特有差异基因，得到肾阳虚证PMOP核心基因群，利用验证基因集评估该基因群中的seed基因对PMOP的诊断效能。使用IRnet算法对肾阳虚证PMOP中的通路重要性以及通路相互作用重要性进行分析。对肾阳虚证PMOP核心基因群进行单细胞基因集分析。利用北京中医药大学第三附属医院住院部病历系统信息以及全国健康和营养调查（NHANES）数据库对肾阳虚证PMOP患者生化相关指标进行7种机器学习分析。利用肾阳虚证PMOP核心基因群进一步预测潜在治疗中药。结果：共获得341个肾阳虚证PMOP特有差异基因及1个肾阳虚证PMOP核心基因群，其seed基因为HOXD3，在验证数据集PMOP组中表达显著上升，具有较高的诊断效能。单细胞基因集分析显示，肾阳虚证PMOP核心基因群可能在骨细胞中高表达。同时，发现RNA降解通路、药物代谢-其他酶通路、鞘脂代谢与半胱氨酸和蛋氨酸代谢、溶酶体与糖胺聚糖降解的相互作用在肾阳虚证PMOP的病理过程中起着重要作用。机器学习分析结果显示，肌酸激酶（CK）与乳酸脱氢酶（LDH）对肾阳虚证PMOP具有较高的诊断效能。此外，还预测得到了36种可能用于治疗肾阳虚证PMOP的中药。结论：肾阳虚证PMOP可能是由于骨细胞参与骨骼和肌肉之间的机械耦联，而使骨生成不足而导致，而预测得到的36种中药对于治疗肾阳虚证PMOP具有重要的参考价值，为中医药干预此类疾病的机制研究提供了一定的方向。
关键词：绝经后骨质疏松症；多组学分析；肾阳虚证；中药预测
Abstract：
Objective: To identify biomarkers and
elucidate the underlying mechanisms of postmenopausal osteoporosis (PMOP) with
kidney-yang deficiency syndrome (KYDS) through multi-omics approaches, and to
explore potential traditional Chinese medicine (TCM) therapeutic strategies.
Methods: PMOP-related microarray datasets with KYDS were retrieved from the
Gene Expression Omnibus (GEO) database. Differential gene expression analysis
was performed using the limma package in R. The MCODE plugin in Cytoscape
3.10.2 was employed to identify core gene clusters specific to KYDS-PMOP, with
diagnostic efficacy of seed genes evaluated using validation datasets. The
IRnet algorithm analyzed pathway significance and interactions. Single-cell
gene set enrichment analysis was conducted for the core gene cluster.
Biochemical markers from hospital records and NHANES database were analyzed
using seven machine learning methods. Potential TCM treatments were predicted
based on the core gene cluster. Results: A total of 341 differentially
expressed genes specific to KYDS-PMOP and one core gene cluster were
identified, with HOXD3 as the seed gene demonstrating significantly upregulated
expression in the PMOP validation dataset and exhibiting high diagnostic
efficacy. Single-cell gene set enrichment analysis revealed predominant
expression of the KYDS-PMOP core gene cluster in osteocytes. Pathway analysis
identified crucial involvement of RNA degradation, drug metabolism-enzyme
pathways, sphingolipid metabolism, cysteine and methionine metabolism, as well
as lysosomal-glycosaminoglycan degradation interactions in KYDS-PMOP
pathogenesis. Machine learning analysis indicated that creatine kinase (CK) and
lactate dehydrogennase (LDH) possess high diagnostic value for KYDS-PMOP. Additionally,
36 potential traditional Chinese medicine (TCM) candidates were predicted for
KYDS-PMOP treatment. Conclusion: KYDS-PMOP pathogenesis may involve
insufficient osteogenesis due to impaired mechanical coupling between bone and
muscle mediated by osteocytes. The predicted 36 TCMs provide valuable
therapeutic references and offer important directions for investigating the
mechanisms of TCM interventions in this condition.
Key words：postmenopausal osteoporosis; multi-omics analysis; kidney-yang deficiency syndrome; traditional Chinese medicine prediction
发布时间：2026-01-04
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