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Ginseng effectively counteracts CP-induced reproductive toxicity, exhibiting pharmacological effects that resemble enhanced orexin signaling. In this study, molecular docking identified ginsenoside Rg1 as the candidate with the highest binding affinity for orexin receptor 1 (OX1R). In CP-treated male mice, Rg1 dose-dependently ameliorated reproductive toxicity, as evidenced by improved sexual behavior, sperm motility and DNA integrity, serum testosterone levels, and testicular histology. These protective effects were significantly attenuated by co-administration of the OX1R antagonist SB-334867. Notably, serum orexin-A levels did not differ significantly across all experimental groups, indicating that Rg1 acts directly on testicular OX1R rather than by elevating circulating orexin-A. Mechanistically, Rg1 restored testicular PI3K\/AKT phosphorylation in an OX1R-dependent manner and preserved glucose transporter 3 and glucose transporter 8 immunoreactivity in germ cells. These findings demonstrate that Rg1 protects against CP-induced reproductive toxicity through OX1R-dependent activation of the PI3K\/AKT pathway and maintenance of glucose transporter-mediated metabolism. Thus, OX1R represents a crucial mechanistic node and Rg1 is a promising adjunct therapy to mitigate chemotherapy-related male infertility.<\/jats:p>","DOI":"10.1093\/reprod\/xaag039","type":"journal-article","created":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T11:35:52Z","timestamp":1774784152000},"source":"Crossref","is-referenced-by-count":0,"title":["The orexinergic system mediates the effects of ginsenoside Rg1 on cyclophosphamide-induced reproductive toxicity"],"prefix":"10.1093","volume":"171","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-0503","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"first","affiliation":[{"name":"Yangzhou University School of Traditional Chinese Medicine, Faculty of Medicine, , Yangzhou,","place":["P.R. 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