Li Lijuan, Tao Mi, Gao Xueyun, Cao Quan, Liao Zejing, Chen Feng, Yusufu Ayinigaer, Nie Haihang, Zeng Ziyue, Huang Kai, Deng Xuan, Gao Ping, Wu Xiaoyan
Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, China.
Department of Nephrology, Zhongnan Hospital, Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, China.
J Transl Med. 2025 Jul 4;23(1):742. doi: 10.1186/s12967-025-06554-8.
Diabetic kidney disease (DKD) is the major cause of chronic kidney failure, with tubulointerstitial fibrosis playing a crucial role in disease development. Identifying fibrosis-related genes is crucial for improving diagnosis and developing novel therapies due to the necessity for early detection and effective treatments.
Genes associated with fibrosis were identified by WGCNA, and a FibrosisScore model was constructed based on ssGSEA scores from two DKD datasets. Essential genes were subsequently confirmed by machine learning and single-cell RNA sequencing (scRNA-seq). Potential therapeutic compounds were identified by screening the ZINC database and confirmed via molecular docking. Critical genes involved in renal fibrosis were analyzed in a streptozotocin (STZ)-induced mouse model of DKD, alongside clinical data from the Nephroseq V5 database.
The FibrosisScore model exhibited strong predictive accuracy in both training and validation datasets (AUCs: 0.803, 0.992, 0.891). Patients classified as high-risk demonstrated an increase in M2 macrophages, whereas those identified as low-risk presented a higher prevalence of pro-inflammatory cells. PROM1 and THY1 were recognized as key genes associated with fibrosis. Single-cell RNA analysis revealed that PROM1 is predominantly expressed in proximal tubule cells, while THY1 is enriched in fibroblasts, indicating their distinct roles in fibrosis progression, with both genes exhibiting high diagnostic accuracy (AUC > 0.9). Immune infiltration analysis of PROM1 was primarily associated with a pro-fibrotic, immunosuppressive environment, while THY1 demonstrated antifibrotic properties. ZINC402830 and ZINC3830400 were screened from the ZINC database and validated through molecular docking. In the STZ mouse model, PROM1 correlated with fibrosis and diminished renal function, whereas THY1 exhibited protective effects.
PROM1 and THY1 were critical diagnostic biomarkers for renal fibrosis in DKD, with PROM1 promoting kidney fibrosis and THY1 providing protective effects. The FibrosisScore model demonstrated robust predictive performance, and molecular docking revealed potential therapeutic modulators for these targets.
糖尿病肾病（DKD）是慢性肾衰竭的主要原因，肾小管间质纤维化在疾病发展中起关键作用。由于早期检测和有效治疗的必要性，鉴定纤维化相关基因对于改善诊断和开发新疗法至关重要。
通过加权基因共表达网络分析（WGCNA）鉴定与纤维化相关的基因，并基于来自两个DKD数据集的单样本基因集富集分析（ssGSEA）分数构建纤维化评分（FibrosisScore）模型。随后通过机器学习和单细胞RNA测序（scRNA-seq）确认关键基因。通过筛选ZINC数据库鉴定潜在的治疗化合物，并通过分子对接进行确认。在链脲佐菌素（STZ）诱导的DKD小鼠模型中分析参与肾纤维化的关键基因，同时分析来自Nephroseq V5数据库的临床数据。
FibrosisScore模型在训练和验证数据集中均表现出强大的预测准确性（AUC分别为0.803、0.992、0.891）。分类为高风险的患者M2巨噬细胞增加，而低风险患者促炎细胞的患病率更高。PROM1和THY1被认为是与纤维化相关的关键基因。单细胞RNA分析显示，PROM1主要在近端小管细胞中表达，而THY1在成纤维细胞中富集，表明它们在纤维化进展中具有不同作用，两个基因均表现出高诊断准确性（AUC>0.9）。PROM1的免疫浸润分析主要与促纤维化、免疫抑制环境相关，而THY1表现出抗纤维化特性。从ZINC数据库中筛选出ZINC402830和ZINC3830400，并通过分子对接进行验证。在STZ小鼠模型中，PROM1与纤维化和肾功能减退相关，而THY1表现出保护作用。
PROM1和THY1是DKD肾纤维化的关键诊断生物标志物，PROM1促进肾纤维化，而THY1具有保护作用。FibrosisScore模型表现出强大的预测性能，分子对接揭示了这些靶点的潜在治疗调节剂。
