PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis

Abstract Glucocorticoid‐induced osteoporosis (GIOP) remains the most prevalent complication compromising bone health in patients undergoing glucocorticoid (GC) therapy. Despite its clinical significance, osteocyte death, a pivotal initiator of GC‐driven bone metabolic imbalance, has received insufficient attention. This study identifies ferroptosis, an iron‐dependent 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‐treated 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‐targeting adeno‐associated virus‐mediated PSMD14 overexpression stabilized SLC7A11, attenuating both osteocytic ferroptosis and bone loss in GIOP mice. Through high‐throughput 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‐targeted therapy as a viable clinical strategy.