Echinacoside alleviates asthenozoospermia by upregulating Sox5‑mediated transcriptional activation of the CatSper gene

Asthenozoospermia (AZS) is one of the most common causes of male infertility, and the decreased expression and function of cation channel of sperm (CatSper) in the sperm contributes to the pathology of AZS. Phenylethanoid glycosides, such as echinacoside (ECH), a compound derived from <i>Cistanche tubulosa</i>, exhibit therapeutic potential for AZS. However, the underlying mechanisms of ECH treatment on AZS remain to be fully elucidated. The ornidazole‑induced AZS model rats (AZS rats) were treated with ECH <i>in vivo</i> and human sperm were exposed to ECH <i>in vitro</i>. Computer‑assisted semen analysis was used to assess sperm motility. The functional characteristics of epididymal sperm were evaluated by analyzing hyperactivation and acrosome reaction. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), western blotting and calcium imaging analyses were used to analyze the expression and function of CatSper channels. In addition, RT‑qPCR, western blotting and chromatin immunoprecipitation‑qPCR were used to investigate the Sex‑determining region Y‑related high‑mobility‑group box family, member 5 (Sox5)‑mediated transcriptional activation of the CatSper gene. It was found that ECH treatment enhanced sperm motility, hyperactivation and acrosome reaction in AZS rats. In addition, ECH upregulated the expression and function of the four α subunits of CatSper channel, CatSper1 to CatSper4, in model rats. Furthermore, ECH treatment increased the protein expression of Sox5 and its binding to the CatSper1 gene promoter region in the testes of AZS rats. <i>In vitro</i> results further suggested that ECH treatment improved sperm motility and CatSper function in the sperm samples from both healthy subjects and patients with idiopathic AZS (iAZS). The present findings suggest that ECH treatment exerts certain therapeutic effects on iAZS through the functional upregulation of CatSper channels in the sperm. These findings position ECH as a promising complementary and alternative medicine therapeutic for enhancing sperm function and managing iAZS in clinical practice. .