Shi Yifeng, Tang Qian, Sheng Sunren, Jiang Hongyi, Jin Chen, Zhou Chencheng, Xie Chenglong, Zheng Lin, Zhang Di, Xu Hui, Xu Cong, Ma Haiwei, Xiang Guangheng, Ni Wenfei, Pan Xiaoyun, Yang Lei, Xu Huazi, Qian Yu, Wu Aimin, Wang Xiangyang, Zheng Gang
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, China.
Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai, 200233, China.
Adv Sci (Weinh). 2025 May 30:e14902. doi: 10.1002/advs.202414902.
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.
糖皮质激素诱导的骨质疏松症（GIOP）仍然是接受糖皮质激素（GC）治疗的患者中影响骨骼健康的最常见并发症。尽管其具有临床重要性，但骨细胞死亡作为GC驱动的骨代谢失衡的关键启动因素，却未得到足够的关注。本研究确定铁死亡，一种铁依赖性调节性细胞死亡机制，为GC微环境中骨细胞的一种新的病理表型。利用GPX4条件性敲除小鼠和药理学铁死亡抑制剂，这项工作表明骨细胞铁死亡会加剧GIOP的进展。代谢组学分析揭示了GC处理的骨细胞中胱氨酸不足和谷胱甘肽耗竭。机制上，GC直接阻止去泛素化酶PSMD14与SLC7A11结合，从而促进SLC7A11泛素化和蛋白酶体降解，这急剧减少了胱氨酸摄取。骨靶向腺相关病毒介导的PSMD14过表达稳定了SLC7A11，减轻了GIOP小鼠的骨细胞铁死亡和骨质流失。通过高通量虚拟筛选，这项工作确定泛硫乙胺为一种有效的PSMD14激活剂，可增强去泛素化酶活性，恢复骨细胞中SLC7A11的表达，并减轻骨质疏松症。总的来说，这项研究阐明了骨细胞铁死亡在GIOP发病机制中的作用和机制，并提出以PSMD14为靶点的治疗作为一种可行的临床策略。
