(Z)-Endoxifen as a Potential Modulator of Utrophin Pathways in Duchenne Muscular Dystrophy: A Mechanistic and Transcriptomic Perspective

Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by mutations in the dystrophin gene, leading to sarcolemmal instability, chronic calcium overload, mitochondrial dysfunction, inflammation, and fibrosis. These effects manifest clinically as muscle atrophy, loss of mobility, and respiratory and cardiac insufficiencies. Although gene-targeted approaches such as exon skipping and microdystrophin delivery have advanced, their applicability is restricted by genotype and adverse effects. Thus, reasonably safe, effective therapies remain a critical unmet need. (Z)-endoxifen, the (Z)-isomer of endoxifen, is the principal active metabolite of tamoxifen, exhibiting higher potency in protein kinase C (PKC) inhibition than tamoxifen and regulating various protein activities differently than tamoxifen. This pharmacologic profile positions endoxifen to address multiple DMD pathological mechanisms simultaneously. Recent literature supports the prior hypothesis that endoxifen exerts pleiotropic benefits in DMD. Transcriptomic and preclinical evidence shows that endoxifen may have superior effects to tamoxifen in reversing DMD signatures given available dosing regimens. Additionally, pathway-level insights support endoxifen activation of myogenesis, oxidative phosphorylation, estrogen receptor beta (ERβ) activation, and inhibition of pro-inflammatory and epithelial-to-mesenchymal transition (EMT) pathways in DMD. These findings suggest (Z)-endoxifen may act on utrophin-linked regulatory axes, thereby potentially contributing to functional compensation for dystrophin deficiency. This provides justification for endoxifen's development as a mutation-agnostic DMD therapeutic approach.