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The mechanisms regulating HSC homeostasis, particularly those involving ribosome biogenesis, remain incompletely understood. Here, we identify DCAF13 as a critical regulator of HSC maintenance by stabilizing RRS1, a key factor in ribosome biogenesis. Conditional deletion of\n                    <jats:italic>Dcaf13<\/jats:italic>\n                    in murine hematopoietic cells results in severe pancytopenia, rapid mortality, and complete HSC depletion in both fetal and adult hematopoietic compartments. We show that DCAF13 deficiency disrupts ribosome assembly and protein synthesis, selectively affecting the translation of mRNAs from genes involved in myeloid differentiation, chromatin remodeling, and erythroid homeostasis. DCAF13 directly binds RRS1 and catalyzes its K27\u2010linked polyubiquitination, a non\u2010degradative post\u2010translational modification that enhances RRS1 protein stability.While\n                    <jats:italic>Dcaf13<\/jats:italic>\n                    deletion activates the p53 pathway,\n                    <jats:italic>Trp53<\/jats:italic>\n                    ablation only partially restores HSC numbers and cell cycle progression, and does not prevent apoptosis and hematopoietic failure, indicating the involvement of both p53\u2010dependent and p53\u2010independent mechanisms. These findings establish a DCAF13\u2010RRS1 axis essential for HSC function, in which DCAF13 acts as an essential regulator of ribosome biogenesis. This work provides molecular insights into the pathogenesis of hematopoietic disorders and ribosomopathies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513777","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:20:54Z","timestamp":1773015654000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DCAF13 Safeguards Hematopoietic Stem Cells via RRS1\u2010Regulated Ribosome Biogenesis"],"prefix":"10.1002","volume":"13","author":[{"given":"Mengke","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Hematology Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital Zhengzhou University People's Hospital  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Wu","sequence":"additional","affiliation":[{"name":"Translational Research Institute Henan International Join 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