Inflammation, a common pathological process, represents an acute response of the body to stimulus (infection, tissue damage, abnormal immune response, etc.). Under physiological conditions, inflammation is triggered automatically with the organism senses acute injury or homeostatic imbalance, which is transient and beneficial to physiology [1]. However, chronic or excessive inflammation may lead to numerous diseases, it is noteworthy that once abnormal inflammation occurs in specific parts or organs can cause serious consequences, such as neuroinflammation can lead to serious central nervous system disorders, serious myocarditis can affect heart function [[2], [3], [4]]. These conditions not only compromise quality of life but also pose life-threatening risks.

Inflammation is a complex pathology that generates multiple damaging cytokines, one mechanism explanation is that the metabolic pathway of arachidonic acid plays a significant role in inflammation. The targeting of inflammatory cytokines structures and their synthetic pathways are viable strategies for developing anti-inflammatory drugs. Currently, there are two traditional types of drugs for the treatment of inflammation: steroidal anti-inflammatory drugs (glucocorticoids, GCs) and non-steroidal anti-inflammatory drugs (NSAIDs) [[5], [6], [7]]. Among them, GCs mainly regulate gene transcription and inhibit various inflammatory mediators, and is mainly used for severe inflammation, allergies and shock. NSAIDs exert anti-inflammatory effects by inhibiting cyclooxygenases (COX) or lipoxygenase (LOX) to reduce the synthesis of prostaglandins and leukotrienes, and are mainly used for mild to moderate inflammation, fever and pain. Although GCs exhibit potent anti-inflammatory effect, long-term use may lead to dependence and severe adverse effects [8,9]. Similarly, NSAIDs also carry risk of cardiovascular complications and alimentary tract hemorrhage [10]. Besides, the abuse of anti-infective for infective inflammation is also a serious medical problem worldwide [11]. In addition to traditional anti-inflammatory drugs, some novel targets for developing anti-inflammation have also shown promising therapeutic efficacy. Tumor necrosis factor α (TNF-α) is primarily produced by activated macrophages and lymphocytes and participates in the maintenance of the immune system and host defense. However, excessive production of TNF-α is closely related to inflammation. Therefore, antibody drugs or small molecule inhibitors developed by neutralizing the activity of TNF-α have been widely studied, such as infliximab (TNF-α inhibitor for Crohn's disease) [12]. Interleukins (IL) are a class of cytokines that play a wide variety of roles in inflammatory responses. Some ILs are regarded as pro-inflammatory cytokines and are used in the development of anti-inflammatory drugs, including ustekinumab (IL-12/23 inhibitor for plaque psoriasis), secukinumab (IL-17 inhibitor for rheumatoid arthritis) and so on [13,14]. However, the administration methods of biologics may reduce patient compliance and limit their convenient use, particularly in chronic inflammatory diseases requiring long-term treatment [15]. The existence of these problems indicate an urgent need for safer and more effective anti-inflammatory small molecule drugs.

Histone modification is one of the important regulatory mechanisms in epigenetics. Among them, histone deacetylases (HDACs) and histone acetyltransferase (HATs) can maintain normal physiological processes by dynamically regulating the acetylation level of histones. HDACs are mainly involved in the cell cycle such as DNA replication, transcription, cell differentiation and so on, and the abnormal function of HDACs could lead to the occurrence of a variety of diseases. The inhibitory effects of histone deacetylase inhibitors (HDACi) on tumor cell migration, invasion and metastasis have been confirmed. To date, seven HDACis, including vorinostat, belinostat, panobinostat, romidepsin, chidamide, entinostat and givinostat [[16], [17], [18], [19], [20], [21], [22]], have been approved for the treatment of cancer-related diseases or Duchenne muscular dystrophy. However, the non-selective inhibition of HDACs caused multiple side-effects, which limited their clinical application [23].

As a member of the histone deacetylases (HDACs) family, HDAC6 (belongs to class IIb) has unique structure and function. Crystal structure analysis revealed that HDAC6 contains 1215 amino acid residues (Fig. 1, A), and its main functional region includes two catalytic domains (CD1 and CD2), and a zinc-finger ubiquitin binding domain (ZnF-UBP) [24]. HDAC6 is mainly located in the cytoplasm, which can not only participate in the acetylation level regulation of histone, but also mediate the deacetylation process of many non-histone substrates located in the cytoplasm, including transcription factors, structural proteins, and inflammatory mediators, such as α-tubulin, cortactin, heat shock protein (HSP90), etc. [25]. Based on the unique structure and substrate diversity, HDAC6 is widely involved in multiple cellular processes of apoptosis, autophagy, cellular morphology regulation, inflammatory effect, protein transport and degradation. Therefore, the abnormal function of HDAC6 is closely related to the occurrence and development of many diseases [26,27]. According to the Cortellis database (hppts://www.cortellis.com), several HDAC6 inhibitors have advanced to clinical trials, with potential therapeutic applications for various diseases potential therapeutic applications for various diseases such as cholangiocarcinoma, multiple myeloma, solid tumors, diabetic neuropathy, and neurological disorders (Fig. 1, B) [[28], [29], [30], [31], [32]]. Although there are no HDAC6 inhibitors under clinical investigation for inflammatory disorders, the database indicates that more than 300 cases of preclinical-stage HDAC6 inhibitors being explored for the treatment of inflammation (Fig. 2), which demonstrates HDAC6 inhibitors have great potential in the field of inflammation treatment.