Givinostat attenuates sepsis-induced myocardial dysfunction by suppressing macrophage inflammation and restoring...

Sepsis, defined as life-threatening multi-organ dysfunction, remains a critical health challenge. Givinostat, an orally active histone deacetylase inhibitor with anti-inflammatory properties, has been approved for the treatment of Duchenne muscular dystrophy. However, its function in sepsis-induced myocardial dysfunction (SIMD) remains unclear. This study demonstrates that Givinostat significantly improves survival and attenuates cardiac injury in both cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-induced SIMD. Givinostat administration markedly alleviated SIMD-induced myocardial inflammation, oxidative stress, and cardiomyocyte apoptosis. Mechanistically, Givinostat suppressed macrophage infiltration into the heart, downregulated CCL7 expression in cardiac macrophages, and enhanced macrophage phagocytic activity. Crucially, the cardioprotective effects of Givinostat were abolished by recombinant CCL7 administration, underscoring a CCL7-dependent mechanism. These findings reveal that Givinostat alleviates SIMD by attenuating macrophage inflammation through suppression of the CCL7/CCR1 signaling pathway and restoration of phagocytic function, highlighting its therapeutic potential for sepsis and SIMD.