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Orthopedic diseases, such as degenerative conditions including intervertebral disc degeneration, osteoporosis, osteoarthritis, and malignant bone tumors like osteosarcoma, all involve imbalances in the immunometabolic microenvironment. The triggering conditions for disulfidptosis, such as high expression of SLC7A11 and glucose deprivation, are highly correlated with the pathaological features of orthopedic diseases and associated immune dysregulation. However, there is currently a lack of systematic understanding regarding the regulatory networks, molecular markers, and intervention strategies of disulfidptosis in orthopedic diseases, and the specific mechanisms by which it contributes to disease onset and progression remain unclear. This review systematically summarizes the bidirectional immunometabolic regulatory molecular mechanisms, pathological associations, and potential therapeutic strategies of disulfidptosis in orthopedic degenerative diseases and bone tumors. By analyzing the immunometabolic regulatory networks of key molecules such as SLC7A11, TXNRD1, and RPN1, we propose immune\u2010aware precision strategies combining disulfidptosis\u2010targeted metabolic intervention with checkpoint blockade immunotherapy. This review fills the gap in the research of disulfidptosis in orthopedic diseases, providing new insights for a deeper understanding of the molecular mechanisms underlying these conditions, while establishing a theoretical framework for developing precise therapeutic strategies based on the regulation of disulfidptosis.<\/jats:p>","DOI":"10.1002\/jcp.70100","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T10:24:17Z","timestamp":1760005457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bidirectional Regulatory Mechanisms of Disulfidptosis Govern Precision Targeting in Degenerative Bone Diseases and Osteosarcoma"],"prefix":"10.1002","volume":"240","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4259-7592","authenticated-orcid":false,"given":"Xiaoming","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Orthopaedics of the First Affiliated Hospital 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