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Despite its clinical significance, osteocyte death, a pivotal initiator of GC\u2010driven bone metabolic imbalance, has received insufficient attention. This study identifies ferroptosis, an iron\u2010dependent regulated cell death mechanism, as a novel pathological phenotype of osteocytes in GC microenvironments. Utilizing GPX4 conditional knockout mice and pharmacological ferroptosis inhibitors, this work demonstrates that osteocyte ferroptosis exacerbates GIOP progression. Metabolomic profiling reveals cystine insufficiency and glutathione depletion in GC\u2010treated osteocytes. Mechanistically, GCs directly impede the deubiquitinase PSMD14 from binding to SLC7A11, thereby promoting SLC7A11 ubiquitination and proteasomal degradation, which sharply diminishes cystine uptake. Bone\u2010targeting adeno\u2010associated virus\u2010mediated PSMD14 overexpression stabilized SLC7A11, attenuating both osteocytic ferroptosis and bone loss in GIOP mice. Through high\u2010throughput virtual screening, this work identifies Pantethine as a potent PSMD14 activator that enhances deubiquitinase activity, restores SLC7A11 expression in osteocytes, and mitigates osteoporosis. Collectively, this study elucidates the role and mechanism of osteocyte ferroptosis in GIOP pathogenesis and proposes PSMD14\u2010targeted therapy as a viable clinical strategy.<\/jats:p>","DOI":"10.1002\/advs.202414902","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:44:39Z","timestamp":1748583879000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid\u2010Induced Osteoporosis by Suppressing Osteocyte Ferroptosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Yifeng","family":"Shi","sequence":"first","affiliation":[{"name":"Key Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou 325000 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