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This study investigated the relationship among UPRmt, the Sirt3\/FOXO3a pathway, and oxidative stress in chicken hepatocytes under Cu exposure. Here, broilers were fed diets containing 11, 110, 220, or 330 mg\/kg Cu for 49 days, and primary hepatocytes were treated with Cu combined with OTC overexpression, Sirt3 agonist ADTL-SA1215, Sirt3 inhibitor 3-TYP, and FOXO3a overexpression or silencing. Cu exposure causes liver injury and activates UPRmt (upregulated HSP60 and LonP1) and was associated with Sirt3\/FOXO3a inhibition. OTC-overexpression-induced UPRmt activation further correlated with Sirt3\/FOXO3a inhibition, decreased antioxidant enzymes (GPX4 and SOD2), increased oxidative markers (8-OhdG and LPO), and aggravated liver injury. Pharmacological and genetic modulation confirmed Sirt3\/FOXO3a as a key downstream mediator. These results suggest that Cu-induced UPRmt activation, association with Sirt3\/FOXO3a inhibition, may disrupt the redox balance and promote hepatocyte injury, providing new insights into Cu hepatotoxicity.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c06846","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:01:48Z","timestamp":1786467708000},"page":"26043-26056","source":"Crossref","is-referenced-by-count":1,"title":["Mitochondrial Unfolded\nProtein Response Regulates\nCopper-Induced Oxidative Stress via a Sirt3\/FOXO3a Signaling Pathway\nin Chicken Hepatocytes"],"prefix":"10.1021","volume":"74","author":[{"given":"Jingling","family":"Yu","sequence":"first","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Huang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Hu","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Wu","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lvyin","family":"Yang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlan","family":"Yu","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianying","family":"Guo","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyue","family":"Han","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4663-0641","authenticated-orcid":true,"given":"Zhaoxin","family":"Tang","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. China, 510642"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8734-4830","authenticated-orcid":true,"given":"Jianzhao","family":"Liao","sequence":"additional","affiliation":[{"name":"South China Agricultural University , , , ,","place":["Guangzhou, Guangdong, P. R. 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Environ. Saf."},{"issue":"7","key":"2026090104475409400_cit29","doi-asserted-by":"publisher","first-page":"613","DOI":"10.2174\/1570159X18666200123165002","article-title":"A New Vision of Mitochondrial\nUnfolded Protein Response to the Sirtuin\nFamily","volume":"18","author":"Weng","year":"2020","journal-title":"Curr. Neuropharmacol."},{"issue":"1","key":"2026090104475409400_cit30","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1136\/rapm-2020-101918","article-title":"SIRT3 alleviates neuropathic\npain by deacetylating FoxO3a in the\nspinal dorsal horn of diabetic model rats","volume":"46","author":"Zhou","year":"2021","journal-title":"Region.\nAnesth. Pain Med."},{"issue":"10","key":"2026090104475409400_cit31","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1089\/ars.2013.5482","article-title":"Regulation\nof MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome\nsignaling networks to aging and carcinogenesis","volume":"20","author":"Tao","year":"2014","journal-title":"Antioxid. Redox Signal."},{"issue":"4","key":"2026090104475409400_cit32","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1128\/MCB.01337-13","article-title":"SirT3 regulates the\nmitochondrial unfolded protein\nresponse","volume":"34","author":"Papa","year":"2014","journal-title":"Mol. Cell. 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Poult. Sci."},{"key":"2026090104475409400_cit36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2019.109710","article-title":"Effects of copper on oxidative stress\nand autophagy in hypothalamus\nof broilers","volume":"185","author":"Liao","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"2026090104475409400_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.145750","article-title":"Hesperidin\nmitigates copper nanoparticle exposure-induced mitochondrial unfolded\nprotein response through the SIRT3-FOXO3A signaling pathway","volume":"320","author":"Wu","year":"2025","journal-title":"Int. J. Biol. 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