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Although Eleutherococcus senticosus fruit extracts exhibit otoprotective potential, their precise bioactive constituents and underlying molecular mechanisms remain elusive. Using network pharmacology and transcriptomic analysis as hypothesis-generating tools, followed by experimental validation, this study identifies chiisanoside (CSS) as a key bioactive compound mitigating d-galactose-induced cellular senescence and auditory impairment, with an optimal effective dose of 25 \u03bcM in vitro (HEI-OC1 cells) and 50 mg\/kg\/day in vivo (oral gavage in C57BL\/6 mice). Mechanistically, the in vitro and in vivo models demonstrate that CSS suppresses age-related auditory decline primarily by targeting the SESN2\/AMPK signaling axis. Specifically, CSS upregulates SESN2 to activate AMPK, which not only enhances autophagy via the mTOR\/ULK1 pathway but also concurrently inhibits the HIF-1\u03b1\/TFRC\/FTH1 cascade. These findings provide mechanistic insights supporting the potential of CSS as a therapeutic candidate in ARHL.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c03599","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:15:04Z","timestamp":1785849304000},"page":"24309-24343","source":"Crossref","is-referenced-by-count":0,"title":["Chiisanoside Ameliorates\n                    <scp>d<\/scp>\n                    -Galactose-Induced\nAge-Related Hearing Loss by Modulating Autophagy and Ferroptosis via\nthe SESN2\/AMPK Axis"],"prefix":"10.1021","volume":"74","author":[{"given":"Haijing","family":"Wang","sequence":"first","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gao","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Bai","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Ningxia Medical University , , ,","place":["Yinchuan, China, 750002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shurong","family":"Qu","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yugang","family":"Gao","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-7410","authenticated-orcid":true,"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]},{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Teng","sequence":"additional","affiliation":[{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]},{"name":"Jilin Agricultural University , , , ,","place":["Changchun, Jilin Province, China, 130118"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2026081208105146900_cit1","doi-asserted-by":"publisher","first-page":"a033217","DOI":"10.1101\/cshperspect.a033217","article-title":"Age-Related Hearing Loss","volume":"9","author":"Bowl","year":"2019","journal-title":"Cold\nSpring Harbor Perspect. 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