Abstract <p>Aberrant activity of histone deacetylases (HDACs) is a pathological phenomenon in several diseases, including Duchenne muscular dystrophy (DMD). In DMD, the upregulation of HDACs is driven by the disassembly of the dystrophin-associated protein complex (DAPC), which, under normal physiological conditions, provides mechanical stability to muscle fibres and acts as a signalling hub anchoring signalling proteins and molecules to their functional sites. In dystrophic muscle, DAPC disassembly causes delocalisation of signalling proteins and, therefore, disrupts signalling pathways. Displacement of epigenetic signalling molecules leads to the uncontrolled activity of HDACs and excessive removal of acetyl groups from histone proteins. Consequently, chromatin becomes tightly bound, preventing the expression of genes involved in muscle homeostasis. The pathological consequences of increased HDAC activity extend beyond muscle fibres, affecting several cell types, translating into a chronically activated immune system, promoting fibrotic and adipose tissue formation and impairing muscle regeneration. Here, we review the current evidence implicating HDACs as a key driver in DMD disease development and progression. We describe the mechanism of HDAC overactivity and the downstream consequences that contribute to the pathogenesis of the disease by disrupting muscle repair and regeneration. Finally, we highlight HDACs as targets for inhibition, offering a novel therapeutic strategy to counteract the multiple pathological events in DMD.</p> Graphical abstract <p></p>