{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:36:07Z","timestamp":1790253367269,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zhejiang Province Key R&amp;D Program","award":["2024C02004"],"award-info":[{"award-number":["2024C02004"]}]},{"name":"Zhejiang Province Key R&amp;D Program","award":["2022YFD1300504"],"award-info":[{"award-number":["2022YFD1300504"]}]},{"name":"National R&amp;D Program of China","award":["2024C02004"],"award-info":[{"award-number":["2024C02004"]}]},{"name":"National R&amp;D Program of China","award":["2022YFD1300504"],"award-info":[{"award-number":["2022YFD1300504"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Zinc (Zn) imbalance\u2014deficiency or overload\u2014is implicated in hepatocyte injury, yet its mechanisms and therapeutic strategies remain incompletely understood. This study investigated Zn dyshomeostasis-induced hepatotoxicity in AML12 hepatocytes and evaluated fisetin\u2019s protective potential in diet-induced Zn overload C57BL\/6 mice for in vivo validation. In AML12 cells, both Zn deficiency and overload impaired hepatocyte viability and promoted oxidative stress, but only overload activated autophagy and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Fisetin, a natural flavonoid with well-documented antioxidant and anti-inflammatory properties, selectively mitigated Zn overload-induced AML12 cytotoxicity and oxidative damage by enhancing autophagic flux and Nrf2 signaling without Zn chelation, while demonstrating no effect on Zn deficiency. Specifically, fisetin required autophagy to sustain Nrf2 activation, as chloroquine abolished its protective effects. In vivo, fisetin administration (200 mg\/kg BW, oral gavage) alleviated Zn overload-associated weight loss and hepatic oxidative damage in mice, paralleling its in vitro effects through reinforced autophagy\u2013Nrf2 axis activation. The autophagy-dependent Nrf2 activation mechanism highlights fisetin\u2019s therapeutic potential for Zn-related liver disorders.<\/jats:p>","DOI":"10.3390\/ijms26114978","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T07:04:28Z","timestamp":1747897468000},"page":"4978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Fisetin Attenuates Zinc Overload-Induced Hepatotoxicity in Mice via Autophagy-Dependent Nrf2 Activation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5091-6429","authenticated-orcid":false,"given":"Feifei","family":"Huang","sequence":"first","affiliation":[{"name":"Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2690-429X","authenticated-orcid":false,"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Breeding for High-Quality Animal Products of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41575-023-00775-2","article-title":"Fetal liver development and implications for liver disease pathogenesis","volume":"20","author":"Lotto","year":"2023","journal-title":"Nat. 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