Diagnostic relevance of Humanin, GAS5 and miR-21/miR-103 in prostate disease risk stratification

This study aimed to evaluate the diagnostic significance of circulating mitochondrial-derived peptides, Humanin and MOTS-c, the long non-coding RNA GAS5, and exosomal microRNAs miR-21 and miR-103 in stratifying prostate diseases, including benign prostatic hyperplasia (BPH), precancerous lesions (PL), and prostate cancer (PCa). These biomarkers were selected based on their established roles in cellular stress responses, apoptosis regulation, inflammation, and tumor progression. A cohort of 375 male patients suspected of prostate cancer were enrolled. Plasma and exosomal levels of Humanin, MOTS-c, GAS5, miR-21, and miR-103 were measured. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve analysis, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and decision tree models. Results showed significant downregulation of Humanin and GAS5 in both PL and PCa compared to BPH, supporting their role in early disease transition. Exosomal miR-21 and miR-103 were significantly upregulated in PCa, with miR-21 exhibiting outstanding discriminative power between BPH and PL (AUC = 1.000) and between PL and PCa (AUC = 0.9932). MOTS-c, a mitochondrial-derived peptide, displayed elevated levels in PL compared to BPH, suggesting its involvement in early malignant transformation. A plasma-only diagnostic model combining Humanin, GAS5, and MOTS-c reached 95% cross-validated classification accuracy across clinical groups. Combination of circulating Humanin, MOTS-c, GAS5, and exosomal miRNAs provides a promising non-invasive biomarker panel for risk stratification in prostate diseases. This integrated molecular approach may enhance diagnostic precision and guide personalized clinical decision-making in prostate cancer management.