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Testosterone replacement therapy alleviates SjD progression, but the exact mode of action is unclear and adverse effects are reported. Our present study found that dihydrotestosterone (DHT) enhances the transcription and expression of aquaporin 5 (AQP5) in human salivary gland epithelial cells via androgen receptor (AR) signaling. The DHT\/AR complex binds to the androgen response element of the AQP5 promoter, upregulating AQP5 expression. Using orchiectomized mice, we observed that reduced levels of DHT resulted in hyposalivation and SjD progression. By screening compounds with similar structures to DHT, we identified that DHT-like ginsenoside Rg3, a natural product, upregulates AQP5 expression in salivary gland epithelial cells via binding with AR. The Rg3\/AR complex acts like DHT\/AR and binds to the androgen response element of the AQP5 promoter to promote AQP5 transcription in salivary gland epithelial cells. Gavage of Rg3 restored saliva secretion and submandibular gland morphology in orchiectomized and nonobese diabetic mice. Transcriptome analysis revealed that Rg3 treatment upregulates saliva secretion\u2013related signaling and downregulates inflammation and immune activation\u2013related signaling in the submandibular glands of orchiectomized mice. In conclusion, our results indicated that Rg3 restores androgen deficiency\u2013triggered xerostomia via AR-mediated AQP5 upregulation.<\/jats:p>","DOI":"10.1177\/00220345241302321","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T23:47:31Z","timestamp":1738712851000},"page":"428-438","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ginsenoside Rg3 Alleviates Xerostomia in Orchiectomized Mice via AR\/AQP5"],"prefix":"10.1177","volume":"104","author":[{"given":"B.","family":"Chen","sequence":"first","affiliation":[{"name":"School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y.","family":"Sun","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Epigenetic, Institute of 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