Seminal-Plasma Molecular Biomarkers as a Liquid Biopsy of Testicular Function: Toward AI-Ready Sperm-Retrieval Prediction in Non-Obstructive Azoospermia

Non-obstructive azoospermia (NOA) is characterized by focal and quantitatively limited spermatogenesis, making preoperative prediction of sperm retrieval difficult. Seminal plasma is a biologically plausible liquid-biopsy compartment because it contains testicular, epididymal and accessory-gland secretions enriched with extracellular vesicles, cell-free nucleic acids, proteins and metabolites. This narrative molecular review examines the mechanisms by which germ-cell-derived molecular cargo reaches the ejaculate and organizes seminal-plasma biomarkers by cargo class and spermatogenic stage. Particular attention is given to extracellular-vesicle non-coding RNAs, cell-free seminal mRNAs, germ-cell-enriched proteins including TEX101 and ECM1, and metabolomic and lipidomic signatures. Although several markers show promising discrimination, most remain discovery-stage, single-center and insufficiently validated. The central argument is that the field should move from isolated biomarker nomination toward locked, stage-mapped multi-analyte panels integrated with clinical and genetic predictors under modern prediction-model standards. Seminal plasma is best viewed not as a ready clinical test, but as a biologically coherent platform for future calibrated, externally validated and artificial-intelligence (AI)-ready sperm-retrieval decision support.