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Publications

Journal Article Ahead of print

PubMed: 40789933 DOI: 10.1038/s41390-025-04171-1

Identification of childhood-onset lupus nephritis through integrative bioinformatics: otoferlin as a novel biomarker.

Pediatr Res

Authors: Xinlei Wu, Xinyue Liang, Yang Li, Siyan Chen, Yuanyuan Xie, Chunyan Hua, Sheng Gao

Affiliations

  • 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.
  • School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • Laboratory Animal Center, Wenzhou Medical University, Wenzhou, China.

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

IMPACT

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.

MeSH

Cells, Genes, Pharmaceutical Preparations, Lupus Nephritis, Biomarkers, Therapeutics, Pediatrics, Nephritis, Gene Expression