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Storage-induced microerythrocytes (SMEs) are morphologically altered senescent RBCs that accumulate during storage and are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified. Using a staining protocol that sorts long-stored SMEs (i.e., CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    ) and morphologically normal RBCs (CFSE\n                    <jats:sup>lo<\/jats:sup>\n                    ), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    RBC membranes. CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    RBCs exhibited decreased proteasome activity and deformability; increased phosphatidylserine exposure, osmotic fragility, and endothelial cell adherence; and were cleared from the circulation during human spleen perfusion ex vivo. Conversely, molecular, cellular, and circulatory properties of long-stored CFSE\n                    <jats:sup>lo<\/jats:sup>\n                    RBCs resembled those of short-stored RBCs. CFSE\n                    <jats:sup>hi<\/jats:sup>\n                    RBCs are morphologically and metabolically altered, have irreversibly oxidized and membrane-relocated proteins, and exhibit decreased proteasome activity. In vitro aging during storage selectively alters metabolism and proteostasis in these storage-induced senescent RBCs targeted for clearance.\n                  <\/jats:p>","DOI":"10.1172\/jci183099","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T12:00:32Z","timestamp":1741694432000},"source":"Crossref","is-referenced-by-count":24,"title":["Proteostasis and metabolic dysfunction characterize a subset of storage-induced senescent erythrocytes targeted for posttransfusion clearance"],"prefix":"10.1172","volume":"135","author":[{"given":"Sandy","family":"Peltier","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR, Paris, France."},{"name":"Universit\u00e9 Paris Cit\u00e9, Institut Imagine, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Paris, 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