Iron Metabolism and Ferroptosis in Skeletal Muscle Disorders

Skeletal muscle relies on tightly regulated iron metabolism to support oxygen transport, mitochondrial respiration and the synthesis of iron-containing enzymes. Iron is stored within ferritin complexes and shuttled through the transferrin–transferrin receptor pathway to maintain cellular homeostasis. Dysregulation of these pathways promotes iron accumulation, free radical generation and lipid peroxidation, culminating in ferroptosis—an iron-dependent form of regulated cell death. In muscle tissue, ferroptotic cell loss contributes to weakness, atrophy and impaired regeneration in conditions such as sarcopenia, muscular dystrophies and neurodegenerative myopathies. At the molecular level, depletion of glutathione and inactivation of glutathione peroxidase 4 compromise defence against lipid hydroperoxides, while aberrant autophagy and mitochondrial dysfunction exacerbate oxidative damage. Understanding the interplay between iron handling, redox balance and membrane integrity has revealed novel targets for therapeutic intervention, including iron chelation, antioxidant supplementation and pharmacological modulators of key ferroptotic regulators. These advances offer promise for preserving muscle mass and function in ageing populations and in patients with chronic muscle disease.

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Iron Metabolism and Ferroptosis in Skeletal Muscle Disorders publication trend

The graph below shows the total number of articles in iron metabolism and ferroptosis in skeletal muscle disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation and membrane damage.

Iron homeostasis: The balanced uptake, storage and export of iron to meet cellular demands while preventing toxicity.

Lipid peroxidation: The oxidative degradation of membrane lipids, leading to loss of membrane integrity.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage proteins, lipids and DNA.

Ferritin: A protein complex that sequesters excess iron in a non-reactive form to prevent oxidative stress.

Glutathione peroxidase 4 (GPX4): An enzyme that reduces lipid hydroperoxides and protects cells from ferroptosis.

References

1. Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects. Bone Research (2025).
2. Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells. Cell Death & Disease (2023).
3. Ferroptosis in a sarcopenia model of senescence accelerated mouse prone 8 (SAMP8). International Journal of Biological Sciences (2021).