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This work evaluated the role of casein kinase 2\u03b1 (CK2\u03b1) and FUNDC1 in high\u2010fat diet (HFD)\u2010evoked MASLD. WT and CK2\u03b1 deletion (CK2\u03b1<jats:italic><jats:sup>\u2010\/\u2010<\/jats:sup><\/jats:italic>) mice were subjected to low fat or HFD for 20 weeks. Global metabolism, AST, ALT, cholesterol, triglycerides, hepatic steatosis, fibrosis, inflammation, mitochondrial injury, mitophagy and ferroptosis were examined. Bioinformatics analysis enriched mitochondria\u2010related pathways in MASLD. Hepatic CK2\u03b1 and FUNDC1 were upregulated and downregulated, respectively, in MASLD patients and HFD\u2010fed mice. HFD led to adiposity, hepatomegaly, hepatic steatosis, fibrosis, inflammation, ferroptosis, mitochondrial injury, elevated hepatic tissue Fe<jats:sup>2+<\/jats:sup>, FAS, CHREBP, SREBP1, PGC1\u03b1, PPAR\u03b1, PPAR\u03b3, SCD1, PEPCK, G6Pase, and DGAT1 as well as downregulated FUNDC1, GPx4, SLC7A11 and NCOA4, the effects (except for NCOA4) were nullified by CK2\u03b1 deletion. FUNDC1 deletion nullified CK2\u03b1 deletion\u2010evoked benefit on hepatic ferroptosis and lipid enzymes. In vitro study using palmitic acid indicated an obligatory role for CK2\u03b1, FUNDC1 and ferroptosis in hepatocyte steatosis. Collectively, our results demonstrated that CK2\u03b1 activation by HFD serves as a trigger for mitochondrial damage, hepatic injury, and pathogenesis of MASLD through FUNDC1 disruption and ferroptosis.<\/jats:p>","DOI":"10.1002\/mco2.70277","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:21:31Z","timestamp":1752218491000},"source":"Crossref","is-referenced-by-count":4,"title":["Casein Kinase 2\u03b1 Ablation Confers Protection Against Metabolic Dysfunction\u2010Associated Steatotic Liver Disease: Role of FUN14 Domain Containing 1\u2010Dependent Regulation of Mitophagy and Ferroptosis"],"prefix":"10.1002","volume":"6","author":[{"given":"Ke","family":"He","sequence":"first","affiliation":[{"name":"Minimally Invasive Tumor Therapies Center Guangdong Second Provincial General Hospital  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixiao","family":"Zhan","sequence":"additional","affiliation":[{"name":"Guangzhou 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