Unravelling deregulated metabolites in seminal plasma of infertile men: a systematic review and bioinformatic analysis.

Male infertility is a multifactorial condition accounting for  50% of infertility cases. Although conventional semen analysis remains the standard method for male infertility diagnosis, it fails to explain 30% of the cases and their underlying molecular causes. Metabolomics offers valuable insights into sperm metabolic dysfunction, enabling the identification of deregulated pathways involved in male infertility. Here, a systematic review including metabolomic studies that compare the seminal plasma metabolome of healthy and infertile men was conducted. A literature search was conducted in PubMed, Scopus, and Web of Science databases following PRISMA guidelines. Twenty metabolomic studies published until December 2025 were included and categorized into four groups: asthenozoospermia, oligozoospermia, obesity, and overall male infertility. A total of 284 metabolites were retrieved, of which eleven (down: L-tyrosine, D-fructose, L-valine, phenylalanine, proline, D-glucose, L-alanine, leucine, sorbitol, L-aspartic acid; up: uridine), six (down: D-fructose, glycine, maleic acid, L-valine, proline, and lysine), and ten (down: L-carnitine, L-tyrosine, L-valine, L-alanine, phenylalanine, proline, D-glucose, leucine, malic acid, and citraconic acid) were altered in asthenozoospermia, obesity, and overall infertility groups, respectively. These metabolites were associated with phenylalanine/tyrosine metabolism, fructose and mannose degradation, and β-oxidation of long-chain fatty acids. A bioinformatic analysis of the enzymes possibly involved in these pathways revealed associations with male infertility phenotypes and key sperm functions, including motility, vitality, and energy metabolism. This study provides a list of metabolites altered in the seminal fluid of infertile men, highlighting their potential as biomarkers of male infertility, and gives insights into the metabolic pathways affected in these conditions.