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By removing the nucleus, RBCs gain greater flexibility, enabling them to traverse narrow capillaries with ease, thereby enhancing the efficiency of oxygen and carbon dioxide transport. This transformation underscores the intricate balance between cellular structure and function essential for maintaining homeostasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Topic<\/jats:title><jats:p>This review delves into the multifaceted enucleation process, outlining its complex steps that encompass protein sorting, vesicle trafficking, cytoskeletal remodeling, and apoptosis regulation, while also exploring the potential of enhancing the enucleation rate of RBCs in vitro. We emphasize the intricate regulation of this process, which is orchestrated by multiple factors. This includes transcription factors that meticulously guide protein synthesis and sorting through the modulation of gene expression, as well as non\u2010coding RNAs that play a pivotal role in post\u2010transcriptional regulation during various stages of RBC enucleation. Additionally, macrophages participate in the enucleation process by engulfing and clearing the extruded nuclei, further ensuring the proper development of RBCs. Although many studies have deeply explored the molecular mechanisms of enucleation, the roles of apoptosis and anti\u2010apoptotic processes in RBC enucleation remain incompletely understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Implication<\/jats:title><jats:p>In this review, we aim to comprehensively summarize the RBC enucleation process and explore the progress made in ex vivo RBC generation. In the future, a deeper understanding of the enucleation process could provide significant benefits to patients suffering from anemia and other related conditions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jha2.1051","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T11:29:50Z","timestamp":1731497390000},"page":"1301-1311","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["New insights into the mechanisms of red blood cell enucleation: From basics to clinical applications"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2040-7133","authenticated-orcid":false,"given":"Qianli","family":"Zhuo","sequence":"first","affiliation":[{"name":"China National Center for Bioinformation  Beijing China"},{"name":"Beijing Institute of Genomics, Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing 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