{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T13:16:25Z","timestamp":1793798185672,"version":"4.6.1"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22178070"],"award-info":[{"award-number":["22178070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22178070"],"award-info":[{"award-number":["22178070"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015956","name":"Special Project for Research and Development in Key areas of Guangdong Province","doi-asserted-by":"publisher","award":["2022B1111080003"],"award-info":[{"award-number":["2022B1111080003"]}],"id":[{"id":"10.13039\/501100015956","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Adequate inner-ear exposure is a key challenge in treating age-related hearing loss (ARHL). Astragaloside IV (AS-IV), the principal saponin of Astragalus membranaceus, has anti-aging activity but poor oral bioavailability; its aglycone cycloastragenol (CAG) may represent a pharmacokinetically optimized active moiety. Methods: We compared the pharmacokinetics, cochlear exposure, and biotransformation of CAG and AS-IV after oral dosing in mice by LC-MS\/MS, and evaluated CAG in a D-galactose-induced accelerated-aging rat model (ABR, hair-cell morphology, redox and cytokine assays) and in D-galactose-stressed HEI-OC1 cells. Results: CAG achieved markedly higher plasma and perfused whole-cochlea exposure than intact AS-IV after equivalent dosing, even after molar-dose normalization. AS-IV was biotransformed to CAG in vivo and in liver microsomes, supporting CAG as a quantitatively important active metabolite. In rats, oral CAG reduced ABR threshold elevation and preserved hair-cell architecture, improved cochlear redox status (higher SOD\/GSH; lower ROS\/MDA), and lowered serum TNF-\u03b1\/IL-6. In HEI-OC1 cells, CAG attenuated mitochondrial membrane-potential loss and apoptosis. Conclusions: At equimolar concentrations, CAG and AS-IV showed comparable protective activity in vitro, indicating that the advantage of CAG resides mainly in its pharmacokinetic profile. CAG thus attenuates auditory dysfunction in an accelerated-aging model with superior exposure, supporting its further development for age-associated hearing disorders.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081037","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:05:19Z","timestamp":1787241919000},"page":"1037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cycloastragenol Provides Pharmacokinetic Advantages over Astragaloside IV with Enhanced Cochlear Exposure and Protection Against Age-Associated Hearing Dysfunction"],"prefix":"10.3390","volume":"18","author":[{"given":"Yaqian","family":"Gao","sequence":"first","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiheng","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7989-6212","authenticated-orcid":false,"given":"Zigui","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchang","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4030-2022","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyun","family":"Du","sequence":"additional","affiliation":[{"name":"School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1002\/jnr.24439","article-title":"Pathology and Mechanisms of Cochlear Aging","volume":"98","author":"Keithley","year":"2020","journal-title":"J. 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