Epigenetics refers to reversible and heritable mechanisms that alter gene expression without altering DNA sequence, including DNA methylation, histone modifications, RNA modifications, and changes in miRNAs [1]. One of the most critical mechanisms of histone post-translational modifications is the regulation of histone acetylation, which occurs at lysine residues. It is catalyzed by histone acetyl transferases (HATs) and histone deacetylases (HDACs) [2]. The balance between HATs and HDACs activities is strongly associated with the pathogenesis cancer, autoimmune diseases and neurodegenerative disorders [3].

To date, eighteen HDAC isozymes have been identified and classified in mammals. Based on their distinct structural features and subcellular localization, HDACs are divided into four classes. Class I (HDAC 1, 2, 3, 8), class IIa (HDAC 4, 5, 7, 9), class IIb (HDAC 6, 10), and class IV (HDAC 11) HDACs are Zn2+-dependent enzymes. Class III HDACs (sirtuins 1–7) are a group of NAD+-dependent enzymes [4]. Zn2+-dependent HDACs comprise four important site-binding domains, a surface-binding region, a hydrophobic channel, a catalytic zinc ion-binding domain, and an adjacent inner lumen. By forming a typical “fish-like” structure, the pharmacophore model of HDAC inhibitors (HDACis) consists of three structural domains, a surface recognition cap region (Cap), a linker that occupies the hydrophobic channel, and a zinc-binding group (ZBG) [5]. SAHA (vorinostat), FK228 (Romidepsin), PDX101 (Belinostat), and LBH589 (Panobinostat) are approved by US FDA for the treatment of lymphomas, multiple myeloma (Fig. 1). Additionally, a lot of HDACis are evaluated in clinical studies [6]. However, the non-selective HDACis usually lead to adverse effects such as cardiotoxicity, thrombocytopenia, fatigue, and nausea/vomiting due to high toxicity and non-specific targeting [7]. In recent years, innovative small molecules such as highly selective HDACis and HDAC-based dual-target inhibitors have been extensively studied to overcome the limitations of pan-HDACis.

Within the HDAC family, HDAC6 plays an pivotal role in regulating critical physiological processes such as cell migration, cell proliferation, stress response, and misfolded protein degradation, owing to its unique molecular structure, substrate diversity, and cytoplasmic localization [8]. Elevated HDAC6 activity is associated with various diseases, including cancer, neurodegenerative disorders, immune disorders and a variety of rare diseases [[9], [10], [11], [12]]. The therapeutic role of selective HDAC6 inhibitors has attracted significant interest in recent decades [13]. Highly selective HDAC6 inhibitors may offer safer therapeutic options by precisely targeting disease-related pathways, thereby reducing off-target effects and toxicity. However, single target drugs can only modulate specific signaling pathways, with the risk of inducing drug resistance. In contrast, dual-targeted therapies represent a promising approach. Dual HDAC6 inhibitors can modulate HDAC6 and other key proteins to reduce drug resistance, improve efficacy and enhance patient compliance. Furthermore, due to the unique biological functions and pharmacophore model of its inhibitors, HDAC6 is an ideal target for multi-target drug design. Thus, HDAC6-based dual-target inhibitors as therapeutic agents has attracted increasing research interest. Herein, we present a review on HDAC6 by focusing on its structure and function, association with diseases, and the research progress of various HDAC6 dual-targeting inhibitors.