Contribution of histone deacetylases (HDACs) to the regulation of histone and non-histone proteins: implications for fibrotic diseases.

Abstract

Histone deacetylases (HDACs) are essential enzymes that play a pivotal role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups from histone and non-histone proteins. This deacetylation is a crucial post-translational modification that influences several cellular processes, such as chromatin remodeling, transcriptional repression, and signal transduction. Recent studies have illuminated the significant involvement of HDACs in the pathogenesis of fibrotic diseases, conditions characterized by the excessive accumulation of extracellular matrix components leading to progressive organ dysfunction and failure. These diseases commonly affect the liver, kidney, heart, lung, and colon. The contribution of HDACs to fibrogenesis is multifaceted, involving the modulation of gene expression that governs inflammatory and fibrotic signaling pathways. Therefore, targeting HDACs with specific inhibitors has emerged as a promising therapeutic strategy to mitigate fibrosis in various organs. HDAC inhibitors (HDACi) can potentially reverse the aberrant gene expression profiles associated with fibrotic diseases by restoring acetylation levels, thus attenuating fibrotic responses. Several HDAC inhibitors, such as vorinostat, trichostatin A, and romidepsin, have shown efficacy in preclinical models of fibrosis, demonstrating their potential to suppress fibrogenic signaling pathways and reduce extracellular matrix deposition. In this review, we provide a comprehensive analysis of the current understanding of the roles of HDACs in the regulation of histone and non-histone proteins, and their implications for fibrotic diseases. We compare the molecular mechanisms by which different classes of HDACs contribute to fibrosis in various organs, and highlight the therapeutic potential of HDAC inhibition. This review underscores the importance of further research into HDAC-specific inhibitors as viable treatments for fibrotic diseases, aiming to develop targeted therapies that can effectively ameliorate fibrosis and improve patient outcomes.