Wu Xinlei, Liang Xinyue, Li Yang, Chen Siyan, Xie Yuanyuan, Hua Chunyan, Gao Sheng
School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China.
School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, China.
Pediatr Res. 2025 Aug 11. doi: 10.1038/s41390-025-04171-1.
Childhood-onset systemic lupus erythematosus (cSLE) exhibits a higher incidence of lupus nephritis (LN) compared to adult-onset SLE (aSLE). However, the underlying molecular mechanisms remain elusive.
Gene expression datasets from childhood-onset (GSE65391) and adult-onset (GSE72798) LN patients were obtained. Differential gene expression (DEG) and weighted gene co-expression network analysis (WGCNA) identified key modules associated with cLN. Machine learning algorithms (random forest, SVM-RFE) prioritized hub genes, validated by ROC curves. Immune cell profiles analysis (CIBERSORT, ssGSEA, xCell) evaluated immune cell profiles, and functional enrichment (GSEA, GSVA) explored pathway alterations. Molecular docking and drug sensitivity analysis predicted therapeutic targets for otoferlin (OTOF)-high cLN.
Distinct gene expression profiles were revealed between cLN and aLN, with significant enrichment of interferon (IFN) pathways in cLN. OTOF emerged as a high diagnostic biomarker for cLN, and was positively correlated with activated dendritic cells and associated with the TLR signaling pathway in cLN. Molecular docking predicted strong binding of OTOF to JAK inhibitors, supported by CMap analysis showing sensitivity of OTOF-high cLN to these drugs.
IFN-related pathways are crucial for the pathogenesis of cLN. OTOF is a promising blood biomarker and contributes to cLN progression through IFN-related pathways.
The molecular mechanisms by which cSLE is more likely to progress to cLN than aSLE are rarely investigated. The crucial role of interferon pathways in cLN pathogenesis is highlighted. OTOF could serve as an early diagnostic biomarker for cLN and promote cLN progression through TLRs. These insights could guide tailored therapeutic strategies for cLN, addressing a critical gap in current clinical management.
与成人系统性红斑狼疮（aSLE）相比，儿童期起病的系统性红斑狼疮（cSLE）的狼疮性肾炎（LN）发病率更高。然而，其潜在的分子机制仍不清楚。
获取儿童期起病（GSE65391）和成人期起病（GSE72798）LN患者的基因表达数据集。差异基因表达（DEG）和加权基因共表达网络分析（WGCNA）确定了与儿童期LN相关的关键模块。机器学习算法（随机森林、支持向量机递归特征消除法）对枢纽基因进行排序，并通过ROC曲线验证。免疫细胞图谱分析（CIBERSORT、单样本基因集富集分析、xCell）评估免疫细胞图谱，功能富集分析（基因集富集分析、基因集变异分析）探索通路改变。分子对接和药物敏感性分析预测了otoferlin（OTOF）高表达的儿童期LN的治疗靶点。
儿童期LN和成人期LN之间显示出不同的基因表达谱，儿童期LN中干扰素（IFN）通路显著富集。OTOF成为儿童期LN的高诊断生物标志物，与活化的树突状细胞呈正相关，并与儿童期LN中的Toll样受体（TLR）信号通路相关。分子对接预测OTOF与JAK抑制剂有强结合，基因表达数据库分析显示OTOF高表达的儿童期LN对这些药物敏感，支持了这一结果。
IFN相关通路对儿童期LN的发病机制至关重要。OTOF是一种有前景的血液生物标志物，并通过IFN相关通路促进儿童期LN的进展。
很少有人研究cSLE比aSLE更易进展为儿童期LN的分子机制。强调了干扰素通路在儿童期LN发病机制中的关键作用。OTOF可作为儿童期LN的早期诊断生物标志物，并通过TLR促进儿童期LN的进展。这些见解可为儿童期LN的定制治疗策略提供指导，填补当前临床管理中的关键空白。
