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Scientists from Kumamoto University have proven that correction of iron metabolism can significantly slow muscle deterioration in facioscapulohumeral muscular dystrophy (FSHD), for which there is still no effective treatment. The work was published in the Journal of Clinical Investigation (JCI).

FSHD is a progressive disease in which muscle weakness begins in the face and shoulder girdle, and then spreads to the arms and legs. The cause of the disease is considered to be abnormal activation of the DUX4 gene in skeletal muscles. It triggers a cascade of pathological processes - oxidative stress, inflammation, and death of muscle cells. Despite the fact that DUX4 has long been considered a key therapeutic target, the mechanisms through which it leads to muscle damage remained not fully understood.

In the new study, scientists focused on iron metabolism - one of the most important factors affecting the level of oxidative stress in cells. Using a genetically modified mouse model of FSHD with controlled DUX4 expression, researchers found that this factor disrupts the intracellular iron balance. As a result, excess iron accumulates in muscle tissue, which triggers ferroptosis - a special type of cell death associated with lipid peroxidation.

Surprisingly, additional administration of iron, both in food and in the form of ferric carboxymaltose - an already approved clinical drug for intravenous administration - did not increase, but, on the contrary, reduced the pathological accumulation of iron in muscles. In treated animals, muscle tissue structure and function improved: grip strength increased, muscle endurance improved, and treadmill running results got better.

The therapeutic effect was observed without suppression of the DUX4 gene itself, which indicates action "downstream" - at the level of metabolic and cellular disorders. Gene activity analysis showed that normalization of iron metabolism suppresses inflammatory and lysosomal processes activated by DUX4, thereby protecting muscles from degradation.

Additionally, scientists identified a promising drug target associated with ferroptosis. In experiments on cells and animals, the ferroptosis inhibitor ferrostatin-1 reduced DUX4 toxicity and improved motor function in mice with an FSHD model.

According to Professor Yusuke Ono from the Institute of Molecular Embryology and Genetics at Kumamoto University, the results indicate iron metabolism as a previously underestimated but extremely important therapeutic target for FSHD. Even if it is impossible to completely suppress DUX4 expression, restoring iron balance can help preserve muscle function.