Targeting Nrf2-mediated regulation of ferroptosis: A novel therapeutic approach for orthopedic diseases

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and has gained increasing attention in the pathogenesis of various diseases. Nrf2, a master regulator of antioxidant defense, plays a pivotal role in ferroptosis by modulating iron metabolism and redox homeostasis. This review systematically summarizes the regulatory mechanisms of Nrf2 in ferroptosis, focusing on its transcriptional control of iron metabolism-related targets and antioxidant systems. Key signaling pathways, including SIRT6/Nrf2/GPX4, p62/KEAP1/Nrf2, and AKT/Nrf2/HO-1, are highlighted for their roles in ferroptosis regulation. We further explore the involvement of Nrf2–ferroptosis in orthopedic diseases such as intervertebral disc degeneration, osteoarthritis, osteoporosis, spinal cord injury, and osteosarcoma, and discuss the therapeutic potential of targeting this axis. The unique contribution of this review lies in integrating the transcriptional regulatory network of Nrf2-mediated ferroptosis with the pathophysiological mechanisms of orthopedic diseases, while providing a comprehensive analysis of its therapeutic potential. By delving into the molecular mechanisms of the Nrf2–ferroptosis axis and comparing them with existing research, this work establishes an important theoretical foundation and research direction for the development of novel targeted therapies for orthopedic disorders, with the potential to bring breakthroughs in their treatment.