Ferroptosis in skeletal muscle: from molecular mechanisms to therapeutic interventions

Abstract

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lethal lipid peroxidation and has emerged as a pivotal regulator of skeletal muscle physiology and pathology. This review systematically delineates the core molecular machinery of ferroptosis, including the system Xc−-glutathione-GPX4 axis, dysregulated iron metabolism, and lipid peroxidation, together with key regulatory networks involving p53, Nrf2, and AMPK. We further highlight the context-dependent roles of ferroptosis in skeletal muscle: during development and regeneration, transient and moderate ferroptotic signaling may facilitate myogenesis and tissue remodeling, whereas sustained or excessive ferroptosis drives satellite cell depletion and impaired regenerative capacity. Pathologically, ferroptosis is implicated in a spectrum of muscle disorders—including sarcopenia, muscular dystrophy, sports-related injuries, and inflammatory myopathies—through mechanisms such as iron overload, oxidative stress, and mitochondrial dysfunction. Finally, we summarize emerging therapeutic strategies targeting ferroptosis, including iron chelators, GPX4 activators, natural compounds, gene-based interventions, and physical exercise, and discuss future directions toward precision medicine and combinatorial approaches. By integrating current evidence, this work provides a comprehensive framework for understanding ferroptosis in skeletal muscle homeostasis and disease and offers insights for the development of novel therapeutic interventions. The translational potential of this article This review establishes ferroptosis as a convergent pathogenic mechanism across muscle disorders, offering a framework for patient stratification by ferrototic signatures. It synthesizes preclinical evidence for pharmacologic inhibitors, natural products, and gene-based interventions, while critically evaluating clinical feasibility, safety, and dosing. A tiered translational roadmap from biomarker validation to early-phase trials is proposed to accelerate bench-to-bedside development.