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According to recent advances in pathophysiological understanding, vascular injury, oxidative stress, and inflammatory storms form a pathogenic cascade leading to osteogenic dysfunction, adipogenic lineage drift of mesenchymal stem cells (MSCs), and epigenetic alterations that exacerbate bone degeneration. Despite improvements in early detection, traditional interventions\u2014including bisphosphonates, hyperbaric oxygen therapy, and surgical decompression\u2014have limited efficacy, particularly in the mid-to-late stages. This review systematically synthesizes emerging regenerative approaches across three domains: (1) Cellular and molecular therapies: Autologous MSC transplantation, exosomes, and apoptotic extracellular vesicles restore osteogenesis, modulate immunity, and promote angiogenesis, while gene-editing technologies such as CRISPR\/Cas9 enhance MSC functionality. (2) Nanobiomaterial synergy: Enzyme-mimetic nanozymes and multifunctional polymeric scaffolds improve lesion targeting, reactive oxygen species clearance, and microenvironmental regulation. (3) Advanced bioengineering: Organoid models and 3D-bioprinted living joint prostheses enable the integration of vascularization, mechanical support, and precise drug delivery, representing transformative strategies in personalized repair. Together, these innovations highlight a future paradigm shift from passive support to active, mechanism-targeted regeneration, offering new hope for structural and functional reconstruction in ONFH. Multidisciplinary integration\u2014bridging materials science, stem cell biology, and digital medicine\u2014will be essential for successfully developing functional cures.<\/jats:p>","DOI":"10.1177\/19373368261460246","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:35:13Z","timestamp":1782538513000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Pathogenesis of and Regenerative Strategies for Osteonecrosis of the Femoral Head"],"prefix":"10.1177","author":[{"given":"Zhengang","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China."},{"name":"Institute of Orthopedics, Chinese PLA General Hospital; Beijing Key Laboratory of Regenerative Medicine in Orthopedics; Key Laboratory of Musculoskeletal Trauma &amp; War Injuries PLA, Chinese PLA General Hospital, Beijing, China."},{"name":"Graduate School, Tianjin Medical University, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Fu","sequence":"additional","affiliation":[{"name":"Institute of Orthopedics, Chinese PLA General Hospital; 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