“ Improving the beneficial effects of HDAC8 inhibition by simultaneously activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy”

: Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder characterized by progressive skeletal muscle degeneration, chronic inflammation, fibrosis, and mitochondrial dysfunction. Although gene- and cell-based therapies hold great promise, significant limitations still restrict their broad application, highlighting the need for complementary pharmacological approaches targeting secondary pathological mechanisms. Histone deacetylase (HDAC) inhibitors and Sirtuin 1 (SIRT1) activators represent promising therapeutic strategies, as HDAC8 is involved in cytoskeletal remodeling, whereas SIRT1 mainly regulates mitochondrial metabolism and energy homeostasis. In this study, we investigated the therapeutic efficacy of combining selective HDAC8 inhibition (PCI-34051) with SIRT1 activation (SRT2104) in a zebrafish model of DMD. Combined treatment significantly improved muscle structure and function, reduced inflammatory cell recruitment, and enhanced mitochondrial activity compared with single-drug administration. Importantly, comparable therapeutic efficacy was achieved using reduced doses of both compounds. Proteomic and acetylomic analyses revealed distinct but complementary molecular signatures induced by the two treatments. HDAC8 inhibition predominantly modulated pathways associated with cytoskeletal organization, epigenetic regulation, ribosome biogenesis, and muscle structural remodeling, whereas SIRT1 activation mainly affected mitochondrial function, oxidative metabolism, amino acid catabolism, and cellular bioenergetics. Overall, these findings demonstrate that combined HDAC8 inhibition and SIRT1 activation effectively ameliorate key pathological features of DMD in zebrafish and provide mechanistic insights into the complementary pathways targeted by the two compounds. This work supports the development of combinatorial epigenetic strategies as potential therapeutic approaches for DMD.