ORIGINAL RESEARCH article
Front. Pediatr.
Sec. Pediatric Endocrinology
A Serum Exosomal Four-miRNA Signature for the Diagnosis of Central Precocious Puberty: A Discovery and Validation Study
Provisionally accepted
- 1Shenzhen Children's Hospital, Shenzhen, China
- 2Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
- 3University of South China Hengyang Medical School, Hengyang, China
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Background: The current diagnosis of central precocious puberty (CPP) relies on the invasive and time-consuming GnRH stimulation test. There is an urgent need for convenient, molecular-level non-invasive biomarkers. This study aimed to characterize serum exosomal miRNA profiles and construct a robust diagnostic model to distinguish treatment-naïve CPP patients from healthy controls. Methods: A prospective study enrolled 120 girls (Healthy Controls, n=60; CPP-naïve, n=60). In the discovery phase, 30 randomly selected samples underwent exosomal small RNA sequencing. Differentially expressed small RNAs were identified using DESeq2, followed by functional enrichment and target gene prediction. Four candidate miRNAs (hsa-miR-6747-3p, hsa-miR-6873-5p, hsa-miR-615-3p, and hsa-miR-6886-3p) were selected and validated by qRT-PCR in the entire cohort (n=120). A multivariate logistic regression model was developed and validated using a split-sample approach (training/validation: 60/60) with 10-fold cross-validation. Results: Sequencing identified 92 differentially expressed small RNAs, predominantly miRNAs. Bioinformatics analysis revealed significant enrichment of the GnRH signaling pathway (FDR = 2.8 × 10⁻¹⁰), with key hub genes including KISS1, IGF1, ESR1, and LEPR. qRT-PCR validation confirmed that the four-miRNA panel was highly consistent with sequencing data (Pearson r = 0.918, P < 0.001). In the independent validation cohort, the diagnostic signature achieved an AUC of 0.912 (95% CI 0.875–0.938), with 91.3% sensitivity and 88.9% specificity. Notably, the diagnostic score showed a significant positive correlation with uterine volume and peak LH levels, reflecting the physiological activation of the HPG axis. Conclusion: This study establishes a novel serum exosomal four-miRNA signature as a highly sensitive and specific non-invasive diagnostic tool for CPP. Beyond diagnostic performance, the signature offers molecular insights connecting circulating markers to the GnRH and metabolic pathways. This model presents a promising alternative to invasive testing and lays a foundation for precision diagnostics in pediatric endocrinology.
Keywords: Biomarker diagnosis, central precocious puberty (CPP), exosome, MicroRNA (miRNA), non-invasive, Pediatric Endocrinology
Received: 10 Oct 2025; Accepted: 12 Dec 2025.
Copyright: © 2025 Wang, Xie, Deng, Zhao, Zhang and Wan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jing Wang
Lisheng Wan
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