Keywords
GPX4
FSP1
Iron chelator (DFO)
Delayed healing of osteoporotic fractures
Perioperative intervention
Submitted : 2025-12-10
Accepted : 2025-12-25
Published : 2026-01-09
Abstract
Delayed healing of osteoporotic fractures is a common and challenging clinical problem, traditionally attributed to insufficient local blood supply. However, recent years have seen increasing attention on the critical role of ferroptosis during the “secondary injury” phase of osteoporotic fractures. Ferroptosis damages chondrocytes through iron overload and lipid peroxidation, having a significant impact on bone repair. This article explores the molecular mechanisms of ferroptosis, focusing on the role of osteoclasts in secreting free iron and the impact of changes in GPX4 and FSP1 expression on ferroptosis regulation, highlighting the significance of ferroptosis chondrocyte subpopulations in fracture healing. It also evaluates the application potential and existing controversies of perioperative intervention strategies such as iron chelators and vitamin K2, discussing the development trends of bone-targeted iron chelating nanoparticles and rapid detection technologies for ferroptosis evaluation. This review aims to provide new theoretical bases and intervention ideas for the treatment of clinical osteoporotic fractures, promoting solutions to delayed fracture healing.
References
Qian X, Pan K, Liang C, et al., 2024, Osteoporotic Thoracolumbar Spine Fractures in the Elderly: Alterations in GNRI and BMP-2 in Delayed Union and Associated Factors. Am J Transl Res, 16(12): 7600–7608.
Lin Y, Shen X, Ke Y, et al., 2022, Activation of Osteoblast Ferroptosis Via the METTL3/ASK1-p38 Signaling Pathway in High Glucose and High Fat (HGHF)-Induced Diabetic Bone Loss. Faseb J, 36(3): e22147.
Xiang S, Zhao L, Tang C, et al., 2024, Icariin Inhibits Osteoblast Ferroptosis Via Nrf2/HO-1 Signaling and Enhances Healing of Osteoporotic Fractures. Eur J Pharmacol, 965: 176244.
Cheng S, Hu X, Sun K, et al., 2024, Local Application of Tanshinone IIA Protects Mesenchymal Stem Cells from Apoptosis and Promotes Fracture Healing in Ovariectomized Mice. J Orthop Surg Res, 19(1): 309.
Liu P, Wang W, Li Z, et al., 2022, Ferroptosis: A New Regulatory Mechanism in Osteoporosis. Oxid Med Cell Longev, 2022: 2634431.
Xiao W, Yike W, Gongwen L, et al., 2025, Ferroptosis-Mediated Immune Responses in Osteoporosis. J Orthop Translat, 52: 116–125.
Maheshwari S, Singh A, Verma A, 2024, Ferroptosis: A Frontier in Osteoporosis. Horm Metab Res, 56(9): 625–632.
Komoto K, Nomoto T, El Muttaqien S, et al., 2021, Iron Chelation Cancer Therapy Using Hydrophilic Block Copolymers Conjugated with Deferoxamine. Cancer Sci, 112(1): 410–421.
Lazaridou M, Christodoulou E, Nerantzaki M, et al., 2020, Formulation and In-Vitro Characterization of Chitosan-Nanoparticles Loaded with the Iron Chelator Deferoxamine Mesylate (DFO). Pharmaceutics, 12(3): 238.
Sun H, Cai R, Zhao M, et al., 2025, Beyond Apoptosis: Exploring Necroptosis, Ferroptosis, and Pyroptosis in Sevoflurane- and Isoflurane-Associated PNDs. IBRO Neurosci Rep, 19: 688–698.
Zeng X, Li J, Yang F, et al., 2022, The Effect of Narcotics on Ferroptosis-Related Molecular Mechanisms and Signalling Pathways. Front Pharmacol, 13: 1020447.
Chen L, Lin Z, Liu L, et al., 2019, Fe(2+)/Fe(3+) Ions Chelated with Ultrasmall Polydopamine Nanoparticles Induce Ferroptosis for Cancer Therapy. ACS Biomater Sci Eng, 5(9): 4861–4869.
Lei L, Yuan J, Yang Q, et al., 2024, Curcumin-Polydopamine Nanoparticles Alleviate Ferroptosis by Iron Chelation and Inhibition of Oxidative Stress Damage. RSC Adv, 14(21): 14934–14941.
Michailidou G, Li Y, Zamboulis A, et al., 2024, A Water-Soluble Chitosan Derivative for the Release of Bioactive Deferoxamine. Int J Mol Sci, 25(2): 913.
Yan D, Wu Z, Qi X, 2023, Ferroptosis-Related Metabolic Mechanism and Nanoparticulate Anticancer Drug Delivery Systems Based on Ferroptosis. Saudi Pharm J, 31(4): 554–568.
Papadopoulou S, Kolokithas-Ntoukas A, Salvanou EA, et al., 2021, Chelator-Free/Chelator-Mediated Radiolabeling of Colloidally Stabilized Iron Oxide Nanoparticles for Biomedical Imaging. Nanomaterials (Basel), 11(7): 1677.
Zhou Q, Meng Y, Le J, et al., 2024, Ferroptosis: Mechanisms and Therapeutic Targets. MedComm, 5(12): e70010.
Lee WC, Dixon SJ, 2025, Mechanisms of Ferroptosis Sensitization and Resistance. Dev Cell, 60(7): 982–993.
Tang D, Chen X, Kang R, et al., 2021, Ferroptosis: Molecular Mechanisms and Health Implications. Cell Res, 31(2): 107–125.
Akiyama H, Carter BZ, Andreeff M, et al., 2023, Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia. Cells, 12(8): 1128.
Heyde CE, Roth A, Putzier M, 2023, Osteoporotic Vertebral Body Fractures. Orthopadie (Heidelb), 52(10): 808–817.
Ma TL, Chen JX, Zhu P, et al., 2022, Focus on Ferroptosis Regulation: Exploring Novel Mechanisms and Applications of Ferroptosis Regulator. Life Sci, 307: 120868.