{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:51:48Z","timestamp":1790794308235,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key projects of Natural Science Research Projects in Colleges and Universities of Anhui Province","award":["2024AH050747"],"award-info":[{"award-number":["2024AH050747"]}]},{"name":"Key projects of Natural Science Research Projects in Colleges and Universities of Anhui Province","award":["2023AH050578"],"award-info":[{"award-number":["2023AH050578"]}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2208085MH202"],"award-info":[{"award-number":["2208085MH202"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basic Medical college in Anhui Medical University","award":["2022YPJH203"],"award-info":[{"award-number":["2022YPJH203"]}]},{"name":"Anhui Medical University Innovation Training Program for International Students in China","award":["GJY202502"],"award-info":[{"award-number":["GJY202502"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hyperuricemia is associated with liver dysfunction, yet its molecular mechanisms remain unclear. This study investigated high uric acid (HUA)-induced hepatocyte injury using a hyperuricemia mouse model (HUM) and uric acid (UA)-treated L02 cells. HUM exhibited elevated aspartate aminotransferase (AST)\/alanine aminotransferase (ALT) and pathological liver changes. Transmission electron microscopy (TEM) confirmed ferroptotic hallmarks, including mitochondrial shrinkage and increased membrane density. UA exposure upregulated NADPH oxidase 4 (NOX4), increased reactive oxygen species (ROS), and promoted lipid peroxidation (LPO), accompanied by intracellular Fe2+ accumulation. Mechanistically, UA increased hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1) expression, subsequently upregulating iron transporters divalent metal transporter 1 (DMT1) and transferrin receptor (TFRC). Deferoxamine (DFO) treatment effectively reversed Fe2+ overload and alleviated oxidative stress. Notably, pharmacological inhibition or genetic knockdown of HIF-2\u03b1 specifically suppressed DMT1 upregulation and restored iron homeostasis, while TFRC expression remained unaffected. Blocking the HIF-2\u03b1\/DMT1 axis significantly reduced LPO and mitochondrial dysfunction. These findings demonstrate that HUA induces hepatocyte ferroptosis through HIF-2\u03b1-mediated DMT1 upregulation, leading to Fe2+ overload and mitochondrial impairment. This study identifies the HIF-2\u03b1\/DMT1 pathway as a key driver of HUA-induced liver injury and a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms27062833","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T08:49:28Z","timestamp":1774255768000},"page":"2833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Uric Acid Induces Hepatocytes Ferroptosis Through HIF-2\u03b1\/DMT1-Mediated Iron Overload"],"prefix":"10.3390","volume":"27","author":[{"given":"Tao","family":"Wang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanbao","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meimei","family":"Guo","sequence":"additional","affiliation":[{"name":"Basic Medical College, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Basic Medical College, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Sim Kah","family":"How","sequence":"additional","affiliation":[{"name":"International College, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2160-7576","authenticated-orcid":false,"given":"Youzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Basic Medical College, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1741-2311","authenticated-orcid":false,"given":"Wenjie","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yanai, H., Adachi, H., Hakoshima, M., and Katsuyama, H. 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