Mocetinostat Ameliorates Pathological Cardiac Hypertrophy via Suppression of Ferroptosis Through Nrf2 Pathway

Histone deacetylase 1 (HDAC1) exacerbates ventricular remodeling and heart failure by promoting myocardial peroxidative damage. Thus, this study aimed to investigate whether the HDAC1 inhibitor mocetinostat alleviates pathological cardiac hypertrophy via suppressing ferroptosis and to elucidate the potential mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Primary cardiomyocytes were stimulated with phenylephrine (PE) to induce hypertrophy and ferroptosis in vitro, with or without mocetinostat treatment. The Nrf2 inhibitor ML385 was used to verify pathway specificity. In vivo, a mouse model of pressure-overload-induced cardiac hypertrophy was established using a transverse aortic constriction (TAC)-induced approach. Mocetinostat was administered to evaluate its therapeutic effects. Ferroptosis markers including lipid peroxidation, iron accumulation, and levels of ferroptosis-related proteins, were assessed. The acetylation and nuclear translocation of Nrf2, as well as the expression of the associated downstream targets (Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroportin, ferritin heavy chain 1 (FTH1), heme oxygenase-1 (HO-1)), were analyzed.

Mocetinostat treatment significantly ameliorated PE-induced cardiomyocyte hypertrophy and ferroptosis in vitro and attenuated TAC-induced cardiac hypertrophy and fibrosis in vivo. Mechanistically, mocetinostat facilitated Nrf2 acetylation and promoted Nrf2 nuclear translocation, leading to the transcriptional activation of downstream antioxidant targets and subsequent inhibition of lipid peroxidation. The protective effects of mocetinostat were abrogated by the Nrf2 inhibitor ML385.

This study demonstrates that mocetinostat attenuates pathological cardiac hypertrophy by inhibiting ferroptosis through activation of the Nrf2 pathway . These findings indicate the potential of mocetinostat as a therapeutic strategy for delaying heart failure progression.