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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: Mechanisms, bone metabolism disruption, and therapeutic strategies
Yao-Bin Wang, Zhi-Peng Li, Peng Wang, Rui-Bo Wang, Yu-Hua Ruan, Zhen Shi, Hao-Yu Li, Jin-Ke Sun, Yang Mi, Cheng-Jin Li, Peng-Yuan Zheng, Chang-Jiang Zhang
Yao-Bin Wang, Zhi-Peng Li, Peng Wang, Rui-Bo Wang, Yu-Hua Ruan, Zhen Shi, Hao-Yu Li, Cheng-Jin Li, Chang-Jiang Zhang, The Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Yao-Bin Wang, Yang Mi, Peng-Yuan Zheng, Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Zhi-Peng Li, Tianjian Advanced Biomedical Laboratory, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Jin-Ke Sun, The Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Co-first authors: Yao-Bin Wang and Zhi-Peng Li.
Co-corresponding authors: Peng-Yuan Zheng and Chang-Jiang Zhang.
Author contributions: Wang YB and Li ZP conceptualized and designed the study; Wang P, Wang RB and Ruan YH conducted the literature review and contributed to the drafting of the manuscript; Shi Z and Li HY designed and drew the illustrative figures; Sun JK, Mi Y, and Li CJ reviewed and revised the manuscript for intellectual content; Zheng PY and Zhang CJ reviewed and finalized the manuscript. All authors have read and approved the final version of the manuscript. Wang YB and Li ZP reviewed and summarized the literature and wrote the first draft of the paper. Both authors made vital and integral contributions to the completion of the project and therefore qualify as co-first authors of the paper. As co-corresponding authors, Zheng PY and Zhang CJ played important and integral roles in the design of the review and the preparation of the manuscript. Zheng PY carried out the study design and applied for and received funding for the research project. Zhang CJ reviewed and corrected the article and supervised the writing process of the manuscript. The collaboration between Zheng PY and Zhang CJ was essential for the publication of this manuscript and therefore qualifies them as co-corresponding authors of the paper.
Supported by Henan Province Key Research and Development Program, No. 231111311000; Henan Provincial Science and Technology Research Project, No. 232102310411; Henan Province Medical Science and Technology Key Project, No. LHGJ20220566 and No. LHGJ20240365; Henan Province Medical Education Research Project, No. WJLX2023079; and Zhengzhou Medical and Health Technology Innovation Guidance Program, No. 2024YLZDJH022.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Chang-Jiang Zhang, Chief Physician, Professor, The Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, No. 3 Kangfu Qianjie, Erqi District, Zhengzhou 450052, Henan Province, China.
changjiangzhang1968@outlook.com
Received: March 6, 2025
Revised: March 22, 2025
Accepted: April 16, 2025
Published online: June 15, 2025
Processing time: 100 Days and 6.3 Hours
Diabetic osteoporosis (DOP) is a common complication in diabetes, driven by hyperglycemia-induced metabolic disturbances, chronic inflammation, and oxidative stress. This review describes the critical role of iron metabolism dysregulation in DOP pathogenesis, focusing on ferroptosis, a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species (ROS) overproduction. Diabetic conditions exacerbate iron overload, impairing osteoblast function and enhancing osteoclast activity, while triggering ferroptosis in bone cells. Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption, synergistically promoting bone loss. Furthermore, chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption, with elevated pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6) and ROS exacerbating cellular dysfunction. Therapeutic strategies targeting iron metabolism (e.g., deferoxamine) and ferroptosis inhibition (e.g., nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation, antioxidants like melatonin) demonstrate potential to mitigate DOP progression. Future research should prioritize personalized interventions, clinical trials of iron chelators and antioxidants, and mechanistic studies to refine therapeutic approaches. This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.
Core Tip: Diabetic osteoporosis (DOP) is becoming increasingly prevalent, driven by global aging and diabetes-related metabolic disturbances. Elevated glucose levels impair osteoblast function and activate osteoclasts via oxidative stress and chronic inflammation, accelerating bone loss. Dysregulated iron metabolism, particularly iron overload, triggers ferroptosis - a novel form of cell death marked by lipid peroxidation and reactive oxygen species production-further exacerbating DOP. Therapeutic strategies targeting iron metabolism and ferroptosis, including antioxidants, iron chelators, and personalized interventions, hold significant potential for improving bone health. Future research should prioritize unraveling underlying mechanisms and refining targeted treatment approaches.
