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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\u2009=\u20091.000) and between PL and PCa (AUC\u2009=\u20090.9932). 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.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10238-025-01810-z","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:12:43Z","timestamp":1754464363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Diagnostic relevance of Humanin, GAS5 and miR-21\/miR-103 in prostate disease risk stratification"],"prefix":"10.1007","volume":"25","author":[{"given":"Donatella","family":"Coradduzza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cruciani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Sibono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Tedde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Zinellu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Maioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio Aligi","family":"Cogoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"De Miglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serenella","family":"Medici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Madonia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Angius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Grosso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciriaco","family":"Carru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"1810_CR1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.eururo.2023.04.021","volume":"84","author":"O Bergengren","year":"2023","unstructured":"Bergengren O, et al. 2022 update on prostate cancer epidemiology and risk factors\u2014a systematic review. 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