Ferroptosis in musculoskeletal disorders: Emerging mechanisms and therapeutic opportunities (Review).

Abstract

Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key mechanism underlying tissue degeneration and impaired regeneration in musculoskeletal disorders. Although ferroptosis is associated with conditions such as tendinopathy, sarcopenia, osteoarthritis and osteoporosis, systematic synthesis connecting molecular mechanisms with disease‑specific contexts and translational implications remains limited. The present review summarizes the fundamental molecular mechanisms of ferroptosis, including iron metabolism dysregulation, lipid peroxidation processes and antioxidant defense systems centered on GPX4 and glutathione. Subsequently, the involvement of ferroptosis across major musculoskeletal diseases was investigated, highlighting how iron imbalance, oxidative stress and age‑related alterations collectively contribute to tissue dysfunction and degeneration. Particular emphasis is placed on aging‑associated changes in iron homeostasis and antioxidant capacity as potential amplifiers of ferroptotic vulnerability in musculoskeletal tissues. Experimental modeling strategies and pharmacological modulation approaches used to investigate ferroptosis in musculoskeletal research are further discussed and their mechanistic relevance and translational challenges are analyzed. Finally, the present review outlines emerging therapeutic perspectives and future research directions aimed at improving the understanding and potential clinical targeting of ferroptosis in musculoskeletal disorders. By providing a structured and integrative synthesis, the present review clarifies the role of ferroptosis at the intersection of iron dysregulation, redox imbalance and musculoskeletal decline.