The role of resveratrol in male spermatogenesis: mechanisms and latest advances in clinical applications.

Resveratrol (RSV), a natural polyphenolic compound, has garnered increasing attention as a potential therapeutic agent for male infertility due to its diverse biological effects, including antioxidant, anti-inflammatory, epigenetic regulation, and gene modulation properties. This review systematically summarizes the mechanisms by which RSV influences different stages of spermatogenesis (Fig. 1), along with recent advances in basic research and clinical applications. Evidence from animal studies indicates that RSV mitigates oxidative stress, suppresses inflammatory responses, and optimizes the testicular microenvironment, resulting in improved sperm count, quality, and motility. Mechanistically, RSV enhances spermatogenesis and sperm function primarily via activation of the Sirtuin 1 (SIRT1)/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) antioxidant pathway, inhibition of NF-κB-mediated inflammation, and regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Furthermore, RSV contributes to sperm maturation, DNA repair, and cell cycle regulation through modulation of gene expression and epigenetic modifications. Despite promising preclinical data, current clinical studies are limited by small sample sizes, heterogeneous designs, and low bioavailability, leaving its clinical efficacy incompletely validated. Future investigations should focus on large-scale, multicenter randomized controlled trials to define optimal dosing, safety, and long-term benefits of RSV in male infertility treatment, as well as its potential synergistic use with other antioxidants, hormonal therapies, or assisted reproductive technologies. Additionally, personalized treatment approaches, improved delivery systems, and comprehensive safety assessments are needed to facilitate clinical translation. In conclusion, RSV represents a natural, multi-targeted candidate with considerable promise for enhancing male fertility, but further rigorous clinical validation is essential for its effective application in reproductive medicine. Fig. 1 Overview of the mechanisms by which resveratrol regulates spermatogenesis.