Ferroptosis in compromised bone healing after trauma: from the iron/ROS microenvironment to non-union and bone defect reconstruction

Compromised bone healing-encompassing osteoporotic fractures, large segmental defects requiring induced membrane technique, infected bone defects, and non-union-remains a significant clinical challenge. Although mechanical, vascular, and infectious factors are well-recognized contributors, the molecular mechanisms underlying cellular dysfunction in these contexts remain incompletely understood. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to impaired bone regeneration. This narrative review synthesizes current evidence on ferroptosis in compromised bone healing. We first outline the core biochemistry of ferroptosis, focusing on iron metabolism, lipid peroxidation, and the GPX4/Nrf2 antioxidant axis. We then characterize the post-traumatic microenvironment as a ferroptosis-permissive niche, where hematoma-derived iron release, inflammatory ROS generation, and ischemia-reperfusion injury converge to create conditions favoring ferroptotic cell death. We subsequently review original studies linking ferroptosis to specific clinical phenotypes, highlighting context-dependent mechanisms: NCOA4-mediated ferritinophagy in osteoporotic and smoking-associated contexts, and macrophage ferroptosis with TNF-α-mediated paracrine suppression of osteogenesis in infected defects. Finally, we discuss therapeutic strategies organized by intervention module-iron homeostasis restoration, lipid peroxidation suppression, GPX4/Nrf2 reinforcement, and multifunctional biomaterial platforms-and articulate design principles for integrating ferroptosis modulation into reconstruction workflows. Ferroptosis represents a mechanistically coherent and therapeutically addressable target in compromised bone healing. Translating these insights into clinical practice will require human tissue validation, optimized intervention timing, and prospective trials with reconstruction-relevant endpoints.