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Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH\u2010associated MAFLD and explored the underlying mechanism(s). Male C57BL\/6 mice were fed a western\u2010type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper\u2013iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA\u2010fed and CuD\u2010fed mice under RA. However, in IH exposure, CuD\u2010fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA\u2010fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD\u2010treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator\u2010activated receptor (PPAR)\u03b1 pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis\u2010promoting factor arachidonyl\u2010CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD\u2010induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH\u2010associated MAFLD.<\/jats:p>","DOI":"10.1096\/fj.202400840r","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T09:59:26Z","timestamp":1720087166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Intermittent hypoxia exacerbates metabolic dysfunction\u2010associated fatty liver disease by aggravating hepatic copper deficiency\u2010induced ferroptosis"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5347-0776","authenticated-orcid":false,"given":"Ruhua","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Key Laboratory of Advanced Interdisciplinary Studies Center The First Affiliated Hospital of Guangzhou Medical University  Guangzhou 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