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 insuffi...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202414902 |
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| author | Yifeng Shi Qian Tang Sunren Sheng Hongyi Jiang Chen Jin Chencheng Zhou Chenglong Xie Lin Zheng Di Zhang Hui Xu Cong Xu Haiwei Ma Guangheng Xiang Wenfei Ni Xiaoyun Pan Lei Yang Huazi Xu Yu Qian Aimin Wu Xiangyang Wang Gang Zheng |
| author_facet | Yifeng Shi Qian Tang Sunren Sheng Hongyi Jiang Chen Jin Chencheng Zhou Chenglong Xie Lin Zheng Di Zhang Hui Xu Cong Xu Haiwei Ma Guangheng Xiang Wenfei Ni Xiaoyun Pan Lei Yang Huazi Xu Yu Qian Aimin Wu Xiangyang Wang Gang Zheng |
| author_sort | Yifeng Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c78c36b640b5424e859c664c4e28a7bc |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-c78c36b640b5424e859c664c4e28a7bc2025-08-23T14:14:42ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202414902PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte FerroptosisYifeng Shi0Qian Tang1Sunren Sheng2Hongyi Jiang3Chen Jin4Chencheng Zhou5Chenglong Xie6Lin Zheng7Di Zhang8Hui Xu9Cong Xu10Haiwei Ma11Guangheng Xiang12Wenfei Ni13Xiaoyun Pan14Lei Yang15Huazi Xu16Yu Qian17Aimin Wu18Xiangyang Wang19Gang Zheng20Key Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Orthopedic Surgery Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital Shanghai 200233 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Orthopaedics Surgery Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical University Lishui 323000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Orthopaedics and Traumatology The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine) Hangzhou 310006 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaKey Laboratory of Orthopaedics of Zhejiang Province Department of Orthopedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325000 ChinaAbstract 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.https://doi.org/10.1002/advs.202414902ferroptosisglucocorticoid‐induced osteoporosisPSMD14SLC7A11ubiquitination |
| spellingShingle | Yifeng Shi Qian Tang Sunren Sheng Hongyi Jiang Chen Jin Chencheng Zhou Chenglong Xie Lin Zheng Di Zhang Hui Xu Cong Xu Haiwei Ma Guangheng Xiang Wenfei Ni Xiaoyun Pan Lei Yang Huazi Xu Yu Qian Aimin Wu Xiangyang Wang Gang Zheng PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis Advanced Science ferroptosis glucocorticoid‐induced osteoporosis PSMD14 SLC7A11 ubiquitination |
| title | PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis |
| title_full | PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis |
| title_fullStr | PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis |
| title_full_unstemmed | PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis |
| title_short | PSMD14 Stabilizes SLC7A11 to Ameliorate Glucocorticoid‐Induced Osteoporosis by Suppressing Osteocyte Ferroptosis |
| title_sort | psmd14 stabilizes slc7a11 to ameliorate glucocorticoid induced osteoporosis by suppressing osteocyte ferroptosis |
| topic | ferroptosis glucocorticoid‐induced osteoporosis PSMD14 SLC7A11 ubiquitination |
| url | https://doi.org/10.1002/advs.202414902 |
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