Multi-Omics discovery and clinical validation of IGFBP2, B2M, and CST3 as a serum biomarker panel for diabetic kidney disease progression

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2026-02-05 Epub Date: 2025-10-28 DOI:10.1016/j.gene.2025.149858

Jianbo Wu , Tong Yin , Zhiguo Zhang , Ruili Yin , Elsayed Metwally , Kun Li , Yongsong Xu , Hongling Zhao , Shuwen Zheng , Lingling Wei , Lijie Zhang , Yan Wang , Longyan Yang

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引用次数: 0

Abstract

Background

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. Current diagnostic markers (e.g., UACR, eGFR) exhibit limitations in sensitivity and specificity, underscoring the need for novel approaches.

Methods

We integrated single-cell RNA sequencing (scRNA-seq) of kidney tissues from 30 individuals (18 healthy, 12 DKD) with serum proteomics data. Cellular heterogeneity and dysregulated pathways were analyzed using Seurat and pathway enrichment analyses. Intercellular communication networks were deciphered via tensor-cell2cell. A LASSO model identified hub genes, followed by robust validation across independent bulk RNA-seq cohorts (Nephrectomy and Nephroseq). Integration with proteomics prioritized three candidate biomarkers—IGFBP2, B2M, and CST3— which were further assessed in murine DKD models (STZ/HFD-induced) and clinical serum samples (n = 139). Drug-target interactions were predicted using ChEMBL and validated by molecular docking.

Results

(1) scRNA-seq revealed aberrant activation of immune pathways and enhanced tubule cell repair in DKD. (2) Cell-cell communication analysis identified 43 hub genes, with 8 genes showing consistent upregulation in glomerular and tubular compartments. (3) Integration of proteomics and transcriptomics pinpointed three serum biomarkers-IGFBP2, B2M, CST3. (4) Longitudinal validation in STZ-induced murine models (n = 16) and human clinical samples (n = 139) confirmed progressive, stage-dependent elevation of all three biomarkers, with late-stage DKD showing the most pronounced elevation versus controls (p < 0.001). (5) Molecular docking predicted high-affinity binding of pramlintide acetate to CST3/IGFBP2 and rivipansel to B2M.

Conclusion

Through a multi-omics approach, we identified IGFBP2/B2M/CST3 as a non-invasive biomarker panel for DKD progression, highlighting their roles as both diagnostic markers and therapeutic targets.

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IGFBP2、B2M和CST3作为糖尿病肾病进展的血清生物标志物的多组学发现和临床验证

背景：糖尿病肾病（DKD）是糖尿病的主要微血管并发症。当前的诊断标记物（如UACR、eGFR）在敏感性和特异性方面存在局限性，强调了对新方法的需求。方法：我们将30人（18人健康，12人DKD）肾脏组织的单细胞RNA测序（scRNA-seq）与血清蛋白质组学数据相结合。使用Seurat和通路富集分析细胞异质性和失调通路。细胞间通信网络通过张量-细胞2细胞被破译。LASSO模型确定了中心基因，随后在独立的大量RNA-seq队列（Nephrectomy和Nephroseq）中进行了稳健验证。与蛋白质组学的整合优先考虑了三个候选生物标志物- igfbp2， B2M和CST3-在小鼠DKD模型（STZ/ hfd诱导）和临床血清样本中进一步评估（n = 139）。使用ChEMBL预测药物-靶标相互作用，并通过分子对接验证。结果：(1)scRNA-seq揭示了DKD中免疫通路的异常激活和小管细胞修复的增强。(2)细胞-细胞通讯分析鉴定出43个枢纽基因，其中8个基因在肾小球和小管间室一致上调。(3)结合蛋白质组学和转录组学，确定了三个血清生物标志物- igfbp2， B2M, CST3。(4)在stz诱导的小鼠模型（n = 16）和人类临床样本（n = 139）中进行的纵向验证证实了所有三种生物标志物的进行性，分期依赖性升高，晚期DKD与对照组相比显示出最明显的升高（p ）结论：通过多组学方法，我们确定了IGFBP2/B2M/CST3作为DKD进展的非侵入性生物标志物，突出了它们作为诊断标志物和治疗靶点的作用。

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来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.