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Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy metabolism and ATP synthesis, maintaining oxygen supply, and facilitating protein synthesis. However, the precise molecular mechanisms underlying iron\u2019s regulation of skeletal muscle growth and development remain elusive. In this study, we demonstrated that the conditional knockout (cKO) of FTH1 in skeletal muscle results in muscle atrophy and impaired exercise endurance. In vitro studies using FTH1 cKO myoblasts revealed notable decreases in GSH concentrations, elevated levels of lipid peroxidation, and the substantial accumulation of Fe2+, collectively implying the induction of ferroptosis. Mechanistically, E3 ubiquitin-protein ligase SMURF1 (SMURF1) acts as an E3 ubiquitin ligase for FTH1, thereby facilitating the ubiquitination and subsequent degradation of FTH1. Consequently, this activation of the ferroptosis pathway by SMURF1 impedes myoblast differentiation into myotubes. This study identifies FTH1 as a novel regulator of muscle cell differentiation and skeletal muscle development, implicating its potential significance in maintaining skeletal muscle health through the regulation of iron homeostasis.<\/jats:p>","DOI":"10.3390\/ijms26031390","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T11:32:32Z","timestamp":1738841552000},"page":"1390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["SMURF1-Induced Ubiquitination of FTH1 Disrupts Iron Homeostasis and Suppresses Myogenesis"],"prefix":"10.3390","volume":"26","author":[{"given":"Xia","family":"Xiong","sequence":"first","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlin","family":"Yu","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenming","family":"Hu","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Pen","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Song","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialei","family":"Chen","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xia","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunshun","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaowu","family":"Yang","sequence":"additional","affiliation":[{"name":"Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00223-014-9915-y","article-title":"Skeletal muscle: A brief review of structure and function","volume":"96","author":"Frontera","year":"2015","journal-title":"Calcif. 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