HDAC3 as an Immunometabolic Rheostat: Molecular Mechanisms of Deacylation Plasticity, Lactylation Dynamics, and Spatiotemporal Regulation

Histone deacetylase 3 (HDAC3) is a key node linking immunometabolism, chromatin regulation, and inflammatory transcriptional programs. Rather than functioning simply as a nuclear deacetylase, HDAC3 output is jointly shaped by corepressor-complex assembly, metabolic and acyl-substrate availability, and compartment-specific substrate access. The identification of lysine lactylation and the discovery of delactylase activity in HDAC1–3 have expanded the mechanistic boundaries of HDAC3, repositioning it from a canonical deacetylase toward an emerging regulatory node involved in the dynamic control of multiple acyl modifications. This review examines the complex-dependent activation of HDAC3, its regulation of nuclear inflammatory transcriptional thresholds, the proposed redistribution of its catalytic output across acetylated and lactylated substrates under increased lactate load, and candidate extra-nuclear non-histone acylation networks involving inflammatory signaling proteins and metabolic enzymes. Current evidence supports bona fide delactylase activity of HDAC3 in biochemical systems; however, whether HDAC3 directly delactylates specific cytoplasmic substrates in physiologically relevant settings requires further validation at the compartmental, site-specific, and functional levels. Viewing HDAC3 as an immunometabolic rheostat helps explain its context-dependent functions in inflammatory homeostasis, acute activation, and metabolic stress, and provides a conceptual basis for developing selective, complex-state-sensitive, and function-stratified HDAC3-targeted strategies.