HDAC3-driven immunometabolic reprogramming in type 2 diabetes and its complications: from enzymatic deacetylation to non-enzymatic scaffolding
TL;DR
This review comprehensively integrates the regulatory mechanisms of HDAC3 in β-cell dysfunction, insulin resistance, mitochondrial impairment, and chronic inflammation, highlighting its pivotal role in the initiation and progression of T2DM.
Abstract
Type 2 diabetes mellitus (T2DM) is driven by the intricate interplay between metabolic dysregulation and chronic inflammation. However, the comprehensive epigenetic mechanisms linking immune dysfunction to metabolic abnormalities remain incompletely understood. Histone deacetylase 3 (HDAC3), which possesses both deacetylase catalytic activity and non-enzymatic scaffold functions, has emerged as a critical regulator of immunometabolic homeostasis. Nevertheless, its coordinated pathogenic roles in T2DM and its multi-organ complications have not been fully elucidated. This review comprehensively integrates the regulatory mechanisms of HDAC3 in β-cell dysfunction, insulin resistance, mitochondrial impairment, and chronic inflammation, highlighting its pivotal role in the initiation and progression of T2DM. We further systematically summarize the shared pathogenic mechanisms mediated by HDAC3 in diabetic cardiomyopathy, nephropathy, retinopathy, encephalopathy, and impaired wound healing. In addition, we focus on precision therapeutic strategies targeting HDAC3, with particular emphasis on recent advances and translational challenges involving microRNAs (miR) and naturally derived HDAC3 inhibitors. Collectively, this review identifies HDAC3 as a central epigenetic hub underlying T2DM and its complications, providing novel mechanistic insights and a theoretical foundation for the development of precision-targeted therapies for diabetes and its associated complications.