Astaxanthin Promotes Spermatogenesis in Mice by Reducing Mitochondrial Oxidative Stress Damage and Regulating Fatty Acid Metabolism and Ferroptosis.

BACKGROUND: Spermatogenesis is a complex process that affects the outcome of fertility. Different types of cellular metabolic processes have both positive and negative effects on sperm production. Exploring new methods to promote spermatogenesis is the best way to improve fertility. This study confirmed the effect of astaxanthin on promoting spermatogenesis through various experiments. OBJECTIVE: To explore new activities of astaxanthin and develop the new methods to promote spermatogenesis. METHODS: Network pharmacology, in vitro cell culture and in vivo experiments were used in this research. The targets and potential signaling pathways of astaxanthin in the treatment of spermatogenesis, the effects on the proliferation and apoptosis of spermatogonial stem cells, and the therapeutic effect on oligoasthenozoospermia in mice induced with cyclophosphamide of astaxanthin were all observed. The ACSL3, VDAC, GPX4, FADS2, GLS2, Steap3, MDA, GSH-Px, and iron ions were detected and analyzed to reveal the potential regulatory mechanisms. RESULTS: Astaxanthin has 52 key targets for treating spermatogenesis, among which the oxidative stress metabolic pathway is one of the most important factors. The sperm concentration and forward motility of the oligoasthenozoospermia model mice fed with astaxanthin were significantly greater than those of the control group. The proliferation rate of spermatogonial stem cells cultured with astaxanthin was also significantly greater than that of quercetin group and the proportion of apoptotic cells was significantly lower. Astaxanthin can reduce ACSL3, MDA, and iron ions in spermatogonial stem cells; increase the expression of Steap3, VDAC, GPX4, GLS2, GSH-Px, and FADS2; and improve ester metabolism to promote spermatogenesis in oligoasthenozoospermia model mice. CONCLUSION: Astaxanthin can regulate the metabolism of fatty acid through the ferroptosis pathway, and reduce the mitochondrial oxidative stress damage, and further regulate FADS2, Steap3, and other factors to promote spermatogenesis.