HDAC6

HDAC6 (histone deacetylase 6) is a unique class IIb histone deacetylase that localizes predominantly in the cytoplasm and preferentially targets non-histone substrates rather than chromatin-associated proteins^[1][2]. HDAC6 regulates fundamental cellular functions through deacetylation of α-tubulin, Hsp90, and ubiquitin-associated protein complexes, thereby controlling microtubule dynamics, protein trafficking, stress responses, and protein quality-control mechanisms^[2][3][4]. Mechanistically, HDAC6 functions at the intersection of the ubiquitin-proteasome system and autophagy-related pathways, where its ubiquitin-binding capability facilitates the processing and clearance of misfolded or aggregated proteins^[3][4]. Therefore, HDAC6 has emerged as an important regulator of cellular proteostasis and cytoskeletal remodeling in both physiological and pathological contexts^[2][3]. In disease models, HDAC6 has been implicated in cancer progression, neurodegenerative disorders, and inflammatory conditions through its effects on cell motility, intracellular transport, protein aggregation, and stress signaling pathways^[2][4][5]. Increased HDAC6 activity promotes α-tubulin deacetylation and influences processes associated with tumor cell migration and metastasis, while modulation of HDAC6 activity alters axonal transport and protein aggregate handling in neurodegenerative disease models^[4][5]. Compared with related HDAC isoforms, HDAC6 is distinguished by its predominantly cytoplasmic localization, preference for non-histone substrates, dual catalytic domains, and zinc-finger ubiquitin-binding domain, features that confer specialized biological functions not shared by most nuclear HDAC family members^[2][5]. For experimental applications, HDAC6-selective inhibitors have become widely used chemical probes because they enable investigation of HDAC6-dependent signaling and protein homeostasis pathways while potentially reducing the off-target effects associated with pan-HDAC inhibition^[3][6].