{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T04:31:37Z","timestamp":1786509097455,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010876","name":"Shanghai University of Traditional Chinese Medicine","doi-asserted-by":"crossref","award":["25KFL64"],"award-info":[{"award-number":["25KFL64"]}],"id":[{"id":"10.13039\/501100010876","id-type":"DOI","asserted-by":"crossref"}]},{"award":["25KFL64"],"award-info":[{"award-number":["25KFL64"]}],"id":[{"id":"https:\/\/ror.org\/00z27jk27","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82305352"],"award-info":[{"award-number":["82305352"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82305352"],"award-info":[{"award-number":["82305352"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sarcopenia is an age-related pathological syndrome characterized by progressive and generalized loss of skeletal muscle mass and function, with muscle atrophy representing its cardinal pathological hallmark. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the pathogenesis of muscle atrophy; however, the precise role of iron dysregulation in sarcopenia remains incompletely understood. In the present study, we identified ferroptosis in D-galactose (D-gal)-induced senescent myoblasts, as evidenced by elevated intracellular iron levels and lipid peroxidation, increased malondialdehyde (MDA) content, and upregulated expression of prostaglandin endoperoxide synthase 2 (PTGS2), 4-hydroxynonenal (4-HNE), and long-chain acyl-CoA synthetase 4 (ACSL4), accompanied by diminished glutathione peroxidase 4 (GPX4), SLC7A11 (xCT), and glutathione (GSH) levels, as well as pronounced mitochondrial damage. Notably, treatment with the iron chelator deferoxamine (DFO) significantly attenuated senescence-associated ferroptosis. Moreover, D-gal-induced senescence in myoblasts was accompanied by reduced ferritin expression and elevated nuclear receptor coactivator 4 (NCOA4) levels, both of which were reversed by autophagy inhibition with 3-methyladenine (3-MA) or NCOA4 knockdown, suggesting that NCOA4-mediated ferritinophagy is involved in senescence-induced iron overload and ferroptosis. Furthermore, senescent myoblasts exhibited increased reactive oxygen species (ROS) generation and mitochondrial impairment, which were attributed to cytosolic iron overload-mediated upregulation of mitoferrin 2 (Mfrn2), thereby promoting mitochondria iron import. Finally, pharmacological inhibition of iron overload or ferroptosis by DFO or ferrostatin-1 (Ferr-1) effectively ameliorated skeletal muscle atrophy and functional decline in aged sarcopenia mice. Collectively, these findings elucidate the mechanistic basis of sarcopenia and highlight potential therapeutic avenues targeting iron dysregulation and ferroptosis.<\/jats:p>","DOI":"10.3390\/cells15161434","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T08:08:53Z","timestamp":1786349333000},"page":"1434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NCOA4-Mediated Ferritinophagy Contributes to Iron Overload-Driven Ferroptosis of Senescent Myoblasts in Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Yan","family":"Huang","sequence":"first","affiliation":[{"name":"Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Qi","sequence":"additional","affiliation":[{"name":"Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Yu","sequence":"additional","affiliation":[{"name":"Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1055\/a-1761-8481","article-title":"The Aging Athlete: Paradigm of Healthy Aging","volume":"43","author":"Gries","year":"2022","journal-title":"Int. J. Sports Med."},{"key":"ref_2","first-page":"94","article-title":"Sarcopenia: Prevalence, mechanisms, and functional consequences","volume":"37","author":"Berger","year":"2010","journal-title":"Interdiscip. Top. Gerontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.3346\/jkms.2022.37.e146","article-title":"A Review of Sarcopenia Pathophysiology, Diagnosis, Treatment and Future Direction","volume":"37","author":"Cho","year":"2022","journal-title":"J. Korean Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1016\/S0140-6736(19)31138-9","article-title":"Sarcopenia","volume":"393","author":"Sayer","year":"2019","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lelievre, P., Sancey, L., Coll, J.L., Deniaud, A., and Busser, B. (2020). Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy. Cancers, 12.","DOI":"10.20944\/preprints202010.0447.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabq4469","DOI":"10.1126\/sciadv.abq4469","article-title":"Iron regulatory protein (IRP)-mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow","volume":"8","author":"Bonadonna","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/jcsm.12685","article-title":"Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia-reperfusion damage","volume":"12","author":"Alves","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1113\/expphysiol.2008.046045","article-title":"Iron injections in mice increase skeletal muscle iron content, induce oxidative stress and reduce exercise performance","volume":"94","author":"Reardon","year":"2009","journal-title":"Exp. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yang, J., Zhang, G., Dong, D., and Shang, P. (2018). Effects of Iron Overload and Oxidative Damage on the Musculoskeletal System in the Space Environment: Data from Spaceflights and Ground-Based Simulation Models. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092608"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41392-024-01969-z","article-title":"Iron homeostasis and ferroptosis in human diseases: Mechanisms and therapeutic prospects","volume":"9","author":"Ru","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nchembio.1416","article-title":"The role of iron and reactive oxygen species in cell death","volume":"10","author":"Dixon","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Du, G., Zhang, Q., Huang, X., and Wang, Y. (2022). Molecular mechanism of ferroptosis and its role in the occurrence and treatment of diabetes. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1018829"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.7150\/ijbs.53126","article-title":"Ferroptosis in a sarcopenia model of senescence accelerated mouse prone 8 (SAMP8)","volume":"17","author":"Huang","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102413","DOI":"10.1016\/j.redox.2022.102413","article-title":"NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells","volume":"55","author":"Zhou","year":"2022","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.bbi.2009.11.015","article-title":"Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death","volume":"24","author":"Grohm","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1038\/s41467-018-04038-6","article-title":"Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy","volume":"9","author":"Yin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1021\/acs.jproteome.4c00939","article-title":"Fisetin Alleviates d-Galactose-Induced Senescence in C2C12 Myoblasts: Metabolic and Gene Regulatory Mechanisms","volume":"24","author":"Zhang","year":"2025","journal-title":"J. Proteome Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1002\/jcsm.13553","article-title":"TRIM16 facilitates SIRT-1-dependent regulation of antioxidant response to alleviate age-related sarcopenia","volume":"15","author":"Guo","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, M.Z., Kong, N., Zhang, G.Y., Xu, Q., Xu, Y., Ke, P., and Liu, C. (2022). The critical role of ferritinophagy in human disease. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.933732"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e13621","DOI":"10.1111\/cpr.13621","article-title":"Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases","volume":"57","author":"Li","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Santana-Codina, N., and Mancias, J.D. (2018). The Role of NCOA4-Mediated Ferritinophagy in Health and Disease. Pharmaceuticals, 11.","DOI":"10.20944\/preprints201809.0148.v1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/978-3-030-62026-4_4","article-title":"The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis","volume":"1301","author":"Gikandi","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102122","DOI":"10.1016\/j.redox.2021.102122","article-title":"Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram\/copper-induced ferroptosis","volume":"46","author":"Ren","year":"2021","journal-title":"Redox Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Li, G., Li, X., Dong, J., and Han, Y. (2021). Electroacupuncture Ameliorates Cerebral Ischemic Injury by Inhibiting Ferroptosis. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.619043"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41580-019-0173-8","article-title":"Mitochondria as multifaceted regulators of cell death","volume":"21","author":"Bock","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ba, T., Zhao, D., Chen, Y., Zeng, C., Zhang, C., Niu, S., and Dai, H. (2022). L-Citrulline Supplementation Restrains Ferritinophagy-Mediated Ferroptosis to Alleviate Iron Overload-Induced Thymus Oxidative Damage and Immune Dysfunction. Nutrients, 14.","DOI":"10.3390\/nu14214549"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112552","DOI":"10.1016\/j.yexcr.2021.112552","article-title":"Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis","volume":"402","author":"Wang","year":"2021","journal-title":"Exp. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dietz, J.V., Fox, J.L., and Khalimonchuk, O. (2021). Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond. Cells, 10.","DOI":"10.3390\/cells10092198"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Baiskhanova, D., and Schafer, H. (2024). The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer. Antioxidants, 13.","DOI":"10.3390\/antiox13060696"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/cdd.2015.158","article-title":"Ferroptosis: Process and function","volume":"23","author":"Xie","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100483","DOI":"10.1016\/j.cophys.2022.100483","article-title":"Mitochondria and ferroptosis","volume":"25","author":"Javadov","year":"2022","journal-title":"Curr. Opin. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100276","DOI":"10.1016\/j.mocell.2025.100276","article-title":"Brief guide to detecting ferroptosis","volume":"48","author":"Kusuma","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tian, Y., Tian, Y., Yuan, Z., Zeng, Y., Wang, S., Fan, X., Yang, D., and Yang, M. (2022). Iron Metabolism in Aging and Age-Related Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073612"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Masaldan, S., Belaidi, A.A., Ayton, S., and Bush, A.I. (2019). Cellular Senescence and Iron Dyshomeostasis in Alzheimer\u2019s Disease. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020093"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jamda.2017.05.026","article-title":"Minerals and Sarcopenia; The Role of Calcium, Iron, Magnesium, Phosphorus, Potassium, Selenium, Sodium, and Zinc on Muscle Mass, Muscle Strength, and Physical Performance in Older Adults: A Systematic Review","volume":"19","author":"Abdelrazek","year":"2018","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/ggi.14770","article-title":"Drug-related sarcopenia as a secondary sarcopenia","volume":"24","author":"Kuzuya","year":"2024","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/gerona\/glac139","article-title":"Age-Related Changes in Skeletal Muscle Iron Homeostasis","volume":"78","author":"Alves","year":"2023","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1039\/C7MT00143F","article-title":"The transferrin receptor: The cellular iron gate","volume":"9","author":"Gammella","year":"2017","journal-title":"Metallomics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/jcsm.12700","article-title":"Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis","volume":"12","author":"Ding","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.21037\/jgo-23-1016","article-title":"The application of graphene oxide and ferroptosis in the diagnosis and treatment of colorectal cancer: A narrative review","volume":"15","author":"Zhou","year":"2024","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, Y.Q., Chang, S.Y., Wu, Q., Gou, Y.J., Jia, L., Cui, Y.M., Yu, P., Shi, Z.H., Wu, W.S., and Gao, G. (2016). The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00308"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wu, H., Wang, F., Ta, N., Zhang, T., and Gao, W. (2021). The Multifaceted Regulation of Mitochondria in Ferroptosis. Life, 11.","DOI":"10.3390\/life11030222"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41420-023-01482-2","article-title":"Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma","volume":"9","author":"He","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jeong, J.Y., Son, Y., Kim, Y., Lee, N., Kim, Y., Heo, Y.J., Choi, S.E., Choi, J., Han, S.J., and Jeon, J. (2025). Deferoxamine prevents dexamethasone-induced muscle atrophy by reducing MuRF1 and atrogin-1. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1582216"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e11597","DOI":"10.1016\/j.heliyon.2022.e11597","article-title":"Preventive effects of the butanol fraction of Justicia procumbens L. against dexamethasone-induced muscle atrophy in C2C12 myotubes","volume":"8","author":"Kim","year":"2022","journal-title":"Heliyon"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1434\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T04:18:56Z","timestamp":1786508336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":48,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15161434"],"URL":"https:\/\/doi.org\/10.3390\/cells15161434","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}