The HDAC family is classified into class I, IIa, IIb and IV, with each subclass exhibiting distinct cellular localization, substrate specificity and functional roles. Members of class I, including HDAC1, HDAC2 and HDAC3, are predominantly localized in the nucleus and serve key roles in regulating gene expression, cell cycle progression and apoptosis. Notably, HDAC3 markedly influences both cell cycle regulation and apoptotic pathways, emerging as a key contributor to tumorigenesis and progression (14). The class IIa subgroup comprises HDAC4, HDAC5, HDAC7 and HDAC9. These enzymes shuttle dynamically between the nucleus and cytoplasm to participate in the modulation of diverse signaling cascades. For instance, HDAC5 and HDAC7 engage with pathways implicated in cancer metastasis, underscoring their oncological relevance (15–17). Class IIb HDACs, represented by HDAC6 and HDAC10, reside primarily in the cytoplasm, where they mediate non-histone deacetylation events, affecting processes such as cell motility and stress responses. Among these, HDAC6 has garnered attention as a promising therapeutic target due to its association with cancer and neurodegenerative disorders (18–20). Class IV histone deacetylase comprises only one isoform, HDAC11. Although the development of selective inhibitors faces numerous challenges due to the lack of crystal structure data, accumulating evidence indicates that this protein is involved in the initiation and progression of tumors and inflammatory diseases. The chemical space, scaffold diversity and key structural features of HDAC11 have been systematically characterized, providing core structural basis and a foundation for the design of selective inhibitors targeting this protein (21). The enzymatic activity of HDAC11 mediates resistance to MEK inhibitors in uveal melanoma, serving as an important molecule driving malignant progression of this tumor (22). In Hodgkin lymphoma cells, HDAC11 plays a central regulatory role in the expression of OX40 ligand, acting as a key factor involved in the formation of the tumor inflammatory microenvironment (23). Structural divergence among HDAC isoforms markedly impacts their interaction profiles with substrates and enzymatic activity. Conserved motifs and specialized domains dictate substrate-binding affinity and specificity, features that are fundamental to their cellular functions. Comprehensive understanding of these classification schemes and structural characteristics is essential in designing selective HDACis, enabling tumor-specific targeting for cancer therapy and other pathologies. Elucidating their precise mechanisms will establish a robust foundation for novel therapeutic interventions in the future (24,25).

HDACs exert a central role in regulating chromatin structure and gene expression by catalyzing the deacetylation of lysine residues on histones. This process induces compaction of chromatin conformation, thereby reducing the accessibility of transcriptional machinery to DNA templates and subsequently repressing the transcriptional activity of tumor suppressor genes. HDAC-mediated histone deacetylation enhances the electrostatic interaction between histones and DNA, rendering the chromatin structure more compact and thereby restricting the binding of transcription factors to gene promoters. This process is one of the key epigenetic mechanisms that regulate gene expression in cancer cells (26).

Aberrant expression of HDACs is implicated in various malignant neoplasms. For example, in hepatocellular carcinoma (HCC), dysregulated histone acetylation drives tumorigenesis and progression by silencing tumor suppressor genes (27,28). Furthermore, HDACs extend their regulatory influence beyond histones through deacetylation of non-histone proteins, including transcription factors, thereby modulating cell signaling pathways and altering transcriptional activity. Such post-translational modifications can either enhance or repress target gene expression involved in cell survival, proliferation and metastasis (29,30). This dual regulatory capacity underscores the pivotal role of HDACs in maintaining chromatin dynamics and cellular signaling networks, establishing them as compelling therapeutic targets for cancer treatment. Additionally, HDACs interact with chromatin-remodeling complexes such as switch defective/sucrose non-fermentable; these interactions are key to preserving chromatin architecture and governing gene expression programs. Notably, recruitment of HDACs to specific genomic loci can displace chromatin remodelers, thereby reinforcing transcriptionally repressive environments (31).

Recent studies have revealed the synergistic role of combinatorial histone modifications in chromatin regulation, offering a novel dimension in understanding HDAC function (32,33). Notably, histone modifications can exert synergistic effects through combinatorial modification coding, while HDAC-mediated deacetylation may disrupt the balance of the acetyl-methyl lysine dual modification, thereby altering chromatin accessibility at transcription start sites. The existence of this acetyl-methyl lysine modification has been confirmed in relevant studies (34). For example, in endometrial carcinoma, HDAC1 forms a complex with enhancer of zeste homolog 2. Through deacetylation-methylation, this complex silences tumor suppressor genes such as p21. HDAC1-mediated histone deacetylation compacts chromatin to create conditions for methylation, therefore blocking cell cycle regulatory pathways (35). Furthermore, HDACs do not act independently in epigenetic regulation, but exhibit a close crosstalk with histone methyltransferases and DNMTs. In acute myeloid leukemia (AML), combining HDACis with DNMT inhibitors (DNMTis) disrupts the epigenetic repressive network, reactivates tumor suppressor genes and inhibits cancer cell proliferation (36). In lung cancer models, the interaction between HDAC3 and lysine-specific demethylase 1 affects enhancer activity by regulating histone H3 lysine 4 monomethylation levels, thus highlighting the key role of crosstalk between HDACs and other epigenetic regulators in tumorigenesis (37).

HDACs interact with key signaling pathways involving factors such as nuclear factor-κB (NF-κB), p53 and heat-shock protein 90 (HSP90), thereby modulating cellular responses to stress and proliferation signals. For instance, within the constitutively activated NF-κB pathway frequently observed in cancer, HDACs exert post-translational modifications on pathway components via deacetylation, which is an action that fosters tumor cell survival and proliferation (38,39). Similarly, the tumor-suppressive functionality of the classical guardian protein p53 undergoes negative regulation by HDACs. Inhibition of p53 transcriptional activity through deacetylation enables cancer cells to evade apoptosis (5,40). A specific example during cancer progression involves crosstalk between HDAC5 and special AT-rich sequence-binding protein 1 (SATB1), a chromatin architect regulating tumor suppressor gene expression. Previous studies have demonstrated that, in lung adenocarcinoma, HDAC5-mediated deacetylation of SATB1 represses tumor suppressor genes thus not only promoting neoplastic growth and metastasis but also conferring chemoresistance (41,42). The aberrant expression patterns of HDACs across multiple malignancies, including lung cancer, underscore their dual role in oncogenic signaling, acting both as drivers of carcinogenesis and promising therapeutic targets (Fig. 1). Deciphering the intricate interactions between HDACs and these key regulators along with associated signaling cascades offers promising avenues for the development of enhanced cancer treatment modalities. Notably, combining HDACis with conventional therapies represents a strategic approach to overcome drug resistance and improve patient outcomes (19,43,44).

In summary, various subtypes of the HDAC family form a mechanism-phenotype regulatory network through chromatin remodeling, non-histone modification and regulation of signaling pathways (such as the NF-κB and p53 pathways). Aberrant activation of class I HDACs (such as HDAC1/3) can promote cell proliferation by silencing tumor suppressor genes. Class II HDACs (such as HDAC5/7) are involved in tumor metastasis through regulating epithelial-mesenchymal transition (EMT) and angiogenesis. The bidirectional role of class IV HDAC11 is dependent on the specificity of the tumor microenvironment. These mechanistic foundations provide a core theoretical framework for subsequent analysis of the functional differences of HDACs in diverse tumor types.

HDACs have emerged as pivotal regulatory factors in the pathogenesis of ovarian cancer, particularly implicated in late-stage diagnosis and chemoresistance (45,46). Dysregulated expression of HDACs is associated with tumor aggressiveness. Their hyperactivation induces chromatin condensation and transcriptional repression of tumor suppressor genes (47,48). This dysregulation markedly contributes to poor clinical outcomes in patients with advanced ovarian cancer by enhancing cancer cell survival under conventional chemotherapy regimens. Notably, elevated expression levels of HDAC9 are associated with adverse prognosis in patients with serous ovarian carcinoma (49). By contrast, this enzyme exhibits tumor-suppressive effects in non-serous subtypes, highlighting histological subtype-specific functionalities among HDAC family members (49). Furthermore, interactions between HDACs and signaling pathways involving forkhead box protein O1 or transforming growth factor-β underscore their role in promoting cell migration and invasion, which are key hallmarks of metastatic progression in ovarian malignancy (50).

At the therapeutic strategy level, HDACis have demonstrated promising potential in pre-clinical studies, exhibiting notable anticancer activity against ovarian cancer cells (51–53). However, clinical trials have reported limitations in the efficacy of HDACis when administered as monotherapy, which is a finding that has driven research into combination regimens to enhance therapeutic outcomes. For example, combining HDACis with other anticancer agents has emerged as a highly prospective approach capable of overcoming the constraints associated with single-agent treatments. This strategy leverages synergistic effects between distinct drugs to amplify therapeutic efficacy while potentially mitigating toxicity associated with high-dose monotherapy (54,55). Recent research has focused on elucidating the combinatorial potential of HDACis with poly(ADP-ribose) polymerase inhibitors (PARPis) and other agents; such regimens have demonstrated enhanced cytotoxic effects in ovarian cancer cell lines (56,57). Furthermore, novel dual-target inhibitors targeting both HDAC and complementary signaling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, are under development, reflecting an evolutionary trend towards increasingly personalized and efficient treatment modalities for ovarian cancer (Fig. 2) (58).

HDACs serve a key role in the pathogenesis of endometrial carcinoma, with their mediated histone deacetylation processes closely associated with tumor invasion and poor clinical outcomes (35). As the most common malignant tumor in the female genital tract, endometrial cancer has a global incidence of ~20.2 per 100,000 women, accounting for 30–40% of all female genital tract malignancies. This tumor typically exhibits an aberrant histone acetylation pattern. Among histone deacetylases, HDAC6 acts as a key member and is highly expressed in 76.8% of endometrial cancer tissues. Such aberrant acetylation serves as a critical factor driving aggressive phenotypes including deep myometrial invasion and lymph node metastasis, as well as advanced-stage disease (46.0% at stages III–IV). It is also closely associated with reduced 5-year disease-free survival (41.3%), representing a key molecular feature underlying poor prognosis (59). Disrupted histone acetylation is strongly associated with high-grade tumors, which are characterized by enhanced invasiveness and metastatic propensity (60). Elevation in HDAC levels is markedly associated with advanced disease stages and diminished survival rates, positioning them as potential prognostic biomarkers (61). Furthermore, upregulation of specific HDAC isoforms (such as HDAC1 and HDAC6) promotes EMT, which enhances cancer cell invasive capabilities. Based on these mechanistic insights, therapeutic strategies targeting HDAC activity emerge as key interventions in restraining tumor progression in endometrial carcinoma (35,62).

The therapeutic potential of HDACis in endometrial carcinoma has garnered notable attention, primarily due to their capacity to induce cell-cycle arrest and apoptosis in cancerous cells. Compounds such as suberoylanilide hydroxamic acid and romidepsin, which are prominent members of the HDACis family, have demonstrated efficacy in pre-clinical models by restoring acetylation levels and reactivating epigenetically silenced tumor suppressor genes (35,60,63). These agents not only suppress tumor growth but also sensitize endometrial cancer cells to conventional chemotherapeutic drugs, thus generating synergistic cytotoxic effects. For instance, combinatorial regimens incorporating HDACis with standard chemotherapy have been reported to enhance DNA damage responses and promote apoptotic pathways in endometrial cancer cell lines (35). Ongoing clinical trials evaluating such combination therapies in patients have yielded preliminary results indicating improved tumor regression rates and overall survival outcomes (35,60,64,65). The strategic deployment of HDACis, particularly when integrated with other treatment modalities, represents a promising approach to enhance therapeutic efficacy and overcome drug resistance in endometrial carcinoma (38,66).

HDACs occupy a central position in the regulatory networks governing glioma cells, particularly regarding ferroptosis (a form of regulated cell death driven by iron-dependent lipid peroxidation) (67). As integral components of this pathway, HDACs directly influence tumor progression and therapeutic responses. Inhibition of HDAC activity elevates both histone and non-histone protein acetylation levels, disrupting cellular homeostasis and promoting ferroptotic cell death in glioma cells (68). This mechanism holds particular importance for glioblastoma, which is characterized by high invasiveness and resistance to conventional therapies. The prevalent dysregulation of iron metabolism observed in gliomas is exacerbated by aberrant upregulation of HDACs, thereby sustaining tumor cell survival and proliferation (69,70).

Targeting HDACs to induce ferroptosis represents a promising therapeutic strategy, as previous studies have demonstrated that HDACis enhance the sensitivity of glioma cells to this form of cell death, simultaneously suppressing tumor growth and potentiating the efficacy of existing treatments (67,71). HDACis have emerged as potential therapeutic agents for glioma due to their ability to alter acetylation status in both histone and non-histone proteins, thereby modulating gene expression profiles and cellular behavior. For example, valproic acid (VPA) exhibits notable antineoplastic effects in in vitro and in vivo models of glioma, demonstrating capabilities to inhibit cell proliferation while increasing responsiveness to radiotherapy and chemotherapy, effects that are likely mediated through the regulation of survival/apoptosis signaling cascades (8,72,73). Mechanistically, HDACis operate via multiple pathways, including reactivating epigenetically silenced tumor suppressor genes, downregulating oncogenic drivers to alter cellular dynamics and driving tumor cell death. Additionally, HDACis contribute to enhancing antitumor immune responses by remodeling the tumor microenvironment and facilitating infiltration of immune effector cells (74,75). Clinically, HDACis have demonstrated promise in improving patient outcomes, particularly for isocitrate dehydrogenase (IDH)-mutant glioma subtypes, where malignant cells display increased sensitivity to HDAC inhibition (76,77). Their therapeutic synergy with immune checkpoint inhibitors further underscores their value in glioma management, while highlighting the increasing demand for personalized medicine based on individualized molecular profiling of tumors.

Osteosarcoma, a highly aggressive bone malignancy predominantly affecting children and adolescents, exhibits HDAC-driven progression through enhanced tumor cell migration and invasion, primarily via regulation of EMT. For example, HDAC6 is markedly upregulated in doxorubicin- and cisplatin-resistant osteosarcoma cells, directly associating with their increased metastatic potential (78). Mechanistically, HDAC6 interacts with estrogen receptor-related proteins to modulate their acetylation status and stability, thereby elevating cancer-cell survival rates and conferring apoptosis resistance (79,80). Furthermore, HDACs contribute to the development of chemoresistance and, therefore, inhibiting their activity restores sensitivity to conventional chemotherapeutics, which is a key finding due to the poor prognosis associated with this aggressive disease despite intensive treatment protocols (81). Elevation of HDAC expression in drug-resistant cell lines underscores their promise as therapeutic targets (79,82). Notably, HDACis such as vorinostat and entinostat synergize with doxorubicin in pre-clinical models, enhancing treatment efficacy (83). These agents exert antitumor effects by altering histone/non-histone acetylation landscapes, including reactivating silenced tumor suppressor genes and activating pro-apoptotic pathways; furthermore, when combined with chemotherapy, HDACis exhibit potent combination therapeutic effects, thereby markedly reducing the viability of osteosarcoma cell lines and inducing their apoptosis (84). Additionally, HDACis impede tumor cell motility and invasion (85), while promoting autophagy-induced autonomous cell death (86). Ongoing clinical trials evaluating the safety and efficacy of HDACis combined with standard chemotherapy aim to overcome chemoresistance, improve response rates and, ultimately, enhance patient outcomes in the future (87,88).

HDACis represent a cornerstone therapeutic class for MM, with regulatory approval from the USA FDA for the clinical use of vorinostat, belinostat and romidepsin. Their mechanism of action involves HDAC suppression to disrupt key pathways governing tumor growth and survival, including inhibition of NF-κB signaling cascades, upregulation of cell cycle regulators (including p21 and p53), downregulation of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and induction of apoptotic programs in myeloma cells (89). Concurrently, HDACis enhance antitumor immunity and promote autophagy-mediated cancer cell clearance (90,91). Therapeutic synergy emerges when HDACis are combined with immunomodulatory agents, conventional chemotherapy or targeted therapies, which markedly improves treatment outcomes in patients with MM. For instance, combinatorial regimens incorporating HDACis with proteasome inhibitors (such as bortezomib) demonstrated increased antimyeloma activity and improved survival rates (92), effectively mitigating drug resistance while simultaneously targeting multiple pathogenic pathways implicated in MM pathogenesis. As a classic HDAC inhibitor, vorinostat in combination with the immunomodulatory drug lenalidomide can enhance lenalidomide-mediated CRBN pathway activity through epigenetic regulation, upregulate the expression of NKG2D ligands and promote the cytotoxic function of NK cells, thereby synergistically inhibiting the proliferation of MM cells (93). When combined with the conventional chemotherapeutic agent bortezomib, vorinostat blocks HDAC-mediated protein deacetylation and jointly inhibits the proteasome/aggregate degradation system with bortezomib, thus overcoming bortezomib resistance and inducing synergistic apoptosis in MM cells (94). The HDAC6 inhibitor ACY-241 in combination with the anti-CD38 targeted therapeutic daratumumab shows unique advantages: It can upregulate CD38 expression on the surface of MM cells, significantly enhance the antibody-dependent cellular cytotoxicity effect of daratumumab and effectively improve the efficiency of targeted elimination of MM cells (95).

HDAC3 is a key regulatory factor in cancer biology. By catalyzing histone deacetylation, it promotes chromatin condensation and represses the transcription of genes associated with the cell cycle and apoptosis, thus disrupting the balance between cell proliferation and death. In colorectal cancer (CRC), HDAC3 regulates cancer stem cell-associated genes, thereby influencing tumor cell plasticity and chemoresistance. Ubiquitin-specific peptidase 38 (USP38) modulates HDAC3 stability, while pharmacological or genetic inhibition of USP38 induces HDAC3 degradation and promotes the development of aggressive tumor phenotypes. These findings suggest that targeting the HDAC3-USP38 axis may be an effective strategy to overcome chemoresistance (96–98). HDAC3 also impacts the tumor microenvironment via an NF-κB/p65-dependent mechanism, which silences the chemokine gene C-X-C motif chemokine ligand 10 (CXCL10), thus impeding CD8⁺ T-cell infiltration and fostering an immunosuppressive microenvironment. This mechanism is particularly prominent in KRAS-mutant lung cancer and represents a major cause of its low response rate to immune checkpoint inhibitors (99). Inhibiting HDAC3 increases CXCL10 expression and its combination with anti-programmed cell death protein-1 (PD-1) antibodies markedly enhances tumor regression and T-cell infiltration (37,100). Additionally, HDAC3 inhibition directly induces apoptosis in cancer cells (including breast and lung cancer). Selective HDAC3 inhibitors have demonstrated notable preclinical efficacy; compared with pan-HDAC inhibitors, HDAC3 inhibitors exhibit fewer off-target effects and optimize the therapeutic index (101–103).

HDAC5 serves a key role in transcriptional regulation and is closely associated with the pathogenesis of various cancer types, including lung adenocarcinoma. The core mechanism is that HDAC5 reduces the transcriptional activity of SATB1 via deacetylation at the K411 residue in lung adenocarcinoma, thereby suppressing the expression of tumor suppressor genes and promoting cancer cell migration (42). Downregulation of SATB1 activity enhances metastatic potential by promoting lung adenocarcinoma cell migration. Pharmacological or genetic inhibition of HDAC5 reverses these effects; this not only impedes tumor cell migration, but also reactivates silenced tumor suppressor genes (42). This positions HDAC5 as a promising therapeutic target to prevent invasiveness and restore key antitumor pathways in lung adenocarcinoma. Furthermore, HDAC5 suppression induces cell-cycle arrest, effectively blocking the uncontrolled proliferation of malignant cells (104–106). This dual functionality (simultaneously blocking metastasis and restricting tumor growth) highlights the therapeutic potential of HDAC5 inhibitors. Since aberrant cell cycle progression constitutes a hallmark of malignancy, targeting HDAC5 offers notable value in cancer therapy (Fig. 3). Such intervention could enhance existing treatment modalities and improve patient outcomes, underscoring the need for further investigation into HDAC5 inhibitors as adjunctive therapeutic agents in oncology (107).

HDAC7 is a key regulator driving tumor growth, metastasis and drug resistance through mechanisms intrinsically associated with angiogenic microenvironment modulation. Evidence has demonstrated that HDAC7 is often upregulated in malignancies such as non-small cell lung cancer (NSCLC) and CRC, where these elevated levels are associated with advanced disease stages and poor clinical outcomes (15,108). In NSCLC specifically, HDAC7 potentiates oncogenic signaling by intersecting with fibroblast growth factor 18 (FGF18) pathways, thus enhancing both proliferative capacity and metastatic spread (15). Mechanistically, HDAC7 stabilizes β-catenin (a central mediator of Wnt signaling), facilitating its nuclear translocation and transcriptional complex formation with transcription factor 4 to activate FGF18 expression (Fig. 4) (15). Targeting this axis could disrupt pro-tumorigenic cascades, highlighting the therapeutic vulnerability of HDAC7.

Beyond cellular autonomy, HDAC7 orchestrates extracellular niche formation via dual regulation of angiogenesis and antitumor immunity within the microenvironment. For instance, its role in macrophage polarization and inflammatory reprogramming notably supports metastatic progression (109,110). By engineering pro-vasculature ecosystems conducive to tumor expansion, HDAC7 creates therapeutic challenges through desmoplastic stroma development. Clinically, HDAC7 can serve as both a prognostic biomarker and a therapeutic target. Its high expression predicts poor survival outcomes in patients with various malignancies, including diffuse large B-cell lymphoma (DLBCL), NSCLC, CRC and breast cancer, and can be used for patient risk stratification (108,111). The core mechanism is that high expression of HDAC7 promotes tumor cell proliferation, anti-apoptosis, invasion and metastasis by activating oncogenic pathways such as NF-κB, PI3K/AKT and β-catenin-FGF18, regulating the EMT process and cell cycle-related proteins. Meanwhile, it remodels the immunosuppressive tumor microenvironment and enhances resistance to cancer therapy. Consequently, high HDAC7 expression is closely associated with adverse pathological features including advanced clinical stage, lymph node metastasis and distant metastasis, ultimately leading to shortened overall survival and progression-free survival in patients with DLBCL, NSCLC, CRC and other malignancies, making it a key molecular marker for predicting poor survival outcomes (108,111). Preclinical models have demonstrated that selective inhibition of HDAC7 can sensitize cancer cells to chemotherapy and immunotherapy by disrupting cell survival-related signaling pathways including PI3K/AKT, NF-κB and Wnt/β-catenin, providing a highly promising combination therapeutic strategy to overcome treatment resistance (2,112).

Previous research has revealed the dual role of HDAC11 in oncology, functioning as either an oncogene or tumor suppressor gene depending on the cancer type and microenvironmental context. In HCC, HDAC11 maintains cancer stemness and confers resistance to sorafenib therapy via the microRNA (miR)-145-5p/HDAC11 axis. Downregulation of miR-145-5p elevates HDAC11 expression, thereby enhancing HCC cell survival and proliferative capacity under therapeutic stress (113,114). Within sorafenib-resistant HCC cell lines, dysregulated HDAC11 is associated with augmented drug metabolism and altered signaling pathways driving metastasis. Furthermore, the regulatory influence of HDAC11 over EMT underscores its importance in metastatic progression across multiple malignancies. Its crosstalk with non-coding RNAs, particularly miR-145-5p, forms a key determinant of treatment response in HCC cells, suggesting that the therapeutic targeting of this axis could improve efficacy and overcome chemoresistance (114,115). Clinically, HDAC11 upregulation is associated with poor prognosis in HCC by sustaining stem-like properties and enabling metabolic adaptation for survival under unfavorable conditions. Mechanistically, miR-145-5p suppression elevates HDAC11 levels, which reinforce sorafenib resistance and metastatic potential; by contrast, pharmacological inhibition of HDAC11 restores miR-145-5p abundance, resensitizing HCC cells to sorafenib while attenuating their metastatic abilities (Fig. 5) (113,116). Adding complexity to its functional repertoire, HDAC11 modulates immune evasion pathways and tumor-stroma interactions within the microenvironment, implying that multidimensional therapeutic strategies against HDAC11 may yield notable clinical benefits (116–118).

HDACis exert antitumor effects by targeting the active site of HDACs or regulating their interaction with substrates to reverse aberrant epigenetic modifications. Marked differences exist in the mechanisms of action and subtype selectivity among different types of HDACis. Classified by chemical structure and mechanism of action, HDACis mainly fall into four categories: i) Hydroxamic acid derivatives (such as vorinostat), which achieve pan-subtype inhibition of class I and II HDACs by chelating zinc ions in the active site of HDACs. In cutaneous T cell lymphoma, hydroxamic acid derivatives can induce excessive histone acetylation to activate the transcription of tumor suppressor genes such as p21 (119,120); ii) benzamide derivatives (such as entinostat), which exhibit higher selectivity for class I HDACs (HDAC1/2/3). In osteosarcoma models, benzamide derivatives enhance the cytotoxicity of the chemotherapeutic drug doxorubicin by specifically inhibiting HDAC3 (83); iii) cyclic peptide derivatives (such as romidepsin), which bind to the active pocket of HDACs via their unique cyclic peptide structure. In MM, cyclic peptide derivatives can downregulate the expression level of the anti-apoptotic protein Bcl-2 by inhibiting the NF-κB signaling pathway (89); and iv) fatty acid derivatives (such as VPA), which inhibit HDAC activity in a non-competitive manner. In glioma, fatty acid derivatives can promote the expression level of ferroptosis-related genes and enhance the radiosensitivity of tumor cells (67,71). Beyond regulating histone acetylation, HDACis also exert pleiotropic effects through non-histone modifications: i) In lung adenocarcinoma, HDACis can acetylate the transcription factor SATB1, enhancing its regulatory activity on tumor suppressor genes and reversing the pro-metastatic effect mediated by HDAC5 (42); and ii) in CRC, HDACis disrupt the interaction between HSP90 and its target proteins [namely, protein kinase B (AKT)] by acetylating HSP90, thereby inhibiting cell proliferation signaling pathways (96). These mechanisms collectively form the molecular basis for the antitumor activity of HDACis and provide a target basis for the development of subtype-selective inhibitors.

The clinical efficacy of HDACis differs notably between hematological malignancies and solid tumors, with marked limitations in monotherapy and combination therapy has become the core strategy to improve therapeutic outcomes. In terms of monotherapy, the USA FDA has approved five HDACis for clinical use, including: i) Vorinostat, which is approved for cutaneous T cell lymphoma, with an objective response rate (ORR) of 30–40%, but it is associated with dose-limiting toxicities such as fatigue and gastrointestinal disturbances (119,120); ii) belinostat and romidepsin, which are used for peripheral T cell lymphoma, with ORRs of 25 and 35%, respectively, but their survival benefits for advanced patients are limited (121,122); iii) panobinostat, which is combined with bortezomib for MM and as monotherapy, its ORR is <20%; therefore, it is only used as a salvage treatment option for drug-resistant patients (89,92); and iv) VPA. Phase II clinical trials of VPA in glioma have reported that monotherapy achieves a disease control rate (DCR) of ~40%, but it fails to markedly prolong the progression-free survival (PFS) of patients (74,75). Overall, HDACi monotherapy has poor efficacy in solid tumors. For example, the ORR of vorinostat monotherapy in ovarian cancer is only 12% and the DCR of romidepsin monotherapy in endometrial cancer is <30% (35,54,55,62). Combination therapy strategies have demonstrated synergistic effects in various tumors. In ovarian cancer, the combination of HDACis and PARPis can inhibit the DNA damage repair pathway, increasing the ORR of patients with wild-type BRCA from 15 to 45% without markedly increasing the risk of myelosuppression (56,57). In osteosarcoma, the combination of vorinostat and doxorubicin can downregulate HDAC6 expression, reverse chemoresistance in tumor cells and increase the DCR from 38 to 65% (83,85). In MM, the triple regimen of panobinostat, bortezomib and dexamethasone can markedly prolong the PFS of patients from 9.5 to 12.5 months (92,123). In glioma, the combination of VPA and immune checkpoint inhibitors (anti-PD-1 antibodies) can enhance the infiltration of CD8⁺ T cells in the tumor microenvironment, increasing the ORR from 18 to 35% (76,77). Furthermore, dual-target inhibitors (for example CUDC-907) that concurrently target HDACs and pathways such as PI3K have exhibited enhanced antitumor activity in preclinical models of ovarian and breast cancer, offering a novel avenue for combination therapy (58,124).

Although HDACis exhibit potential in combination therapy, their clinical translation is limited by three core challenges, namely: i) Drug resistance; ii) off-target toxicity; and iii) a lack of biomarkers. Drug resistance is the primary cause of HDACi treatment failure, with three main mechanisms, including: i) Compensatory upregulation of HDAC subtypes. For example, in AML, prolonged use of pan-HDACis leads to increased HDAC3 expression, which maintains tumor cell survival via enhancement of NF-κB pathway activity (98,125). In osteosarcoma, HDAC6 expression is markedly higher in doxorubicin-resistant cell lines compared with that in doxorubicin-sensitive cells, thus contributing to doxorubicin resistance. This phenotype can be reversed by combination with HDAC6-selective inhibitors (79,85); ii) adaptive activation of signaling pathways. For instance, HDACi treatment induces PI3K/AKT pathway activation in lung cancer (102) and triggers compensatory NF-κB pathway activation in MM (89,92); and iii) tumor microenvironment remodeling, such as increased infiltration of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer following HDACi treatment (126). Furthermore, tumor genomic heterogeneity driven by abnormal mutagenic processes exacerbates HDACi resistance; HDAC dysregulation may impair DNA repair capacity, forming an epigenetic dysregulation, which leads to genomic instability, and in turn induces the drug resistance cascade (127). Off-target toxicity limits dose escalation of HDACis. Due to a lack of subtype selectivity, pan-HDACis cause multi-organ adverse effects, including thrombocytopenia (30%) and neutropenia (25%) in the hematological system (128,129); gastrointestinal disturbances (45%) in the digestive system (130); and grade 3+ fatigue (30%) in systemic reactions (131). The grading and classification of adverse events in this article were based on the Common Terminology Criteria for Adverse Events, the universal standard in clinical oncology. Clinically, adverse effects are mitigated by adjusted dosing regimens (such as twice-weekly vorinostat, low initial dose with gradual escalation of VPA) (74,128) or combination with symptomatic drugs. Certain HDACis (such as vorinostat) also carry cardiotoxicity risk (QT interval prolongation) (120). The absence of biomarkers hinders precise patient stratification. No clear molecular biomarkers for the prediction of HDACi efficacy exist. The correlation between HDAC9 expression and HDACi sensitivity in ovarian cancer (49,50), IDH mutation status and HDACi efficacy in glioma (76,77) and p53 mutation and HDACi-bortezomib synergy in MM (89) remain unconfirmed, leading to treatment blindness and increased ineffective treatment rates.

To address the challenges in the clinical translation of HDACis, current research focuses on three key directions: i) Structural modification; ii) targeted delivery; and iii) optimization of combination strategies, aiming to enhance the selectivity and efficacy of HDACis while reducing toxicity.

Structural modification is key to developing subtype-selective HDACis. HDAC3 inhibitors, with an introduced isoquinoline structure, inhibit tumor growth in CRC models without affecting platelet production (103,132). HDAC6 inhibitors, with optimized hydroxamic acid side chain lengths, reduce metastasis rates in triple-negative breast cancer (TNBC) without causing notable gastrointestinal toxicity (18,133). Thiophene derivatives (as HDAC11 inhibitors) can reverse sorafenib resistance in HCC (21,113,114). By contrast, the novel mechanism by which kelch repeat and BTB domain-containing 4 mutations disrupt the ubiquitin-dependent regulation of HDACs suggests that HDAC drug development should consider both HDAC catalytic activity and regulatory networks (134). Furthermore, proteolysis-targeting chimeras (PROTACs) technology enables specific degradation of HDAC subtypes. For example, HDAC7 PROTACs inhibit tumors with low toxicity in lymphoma and overcome compensatory HDAC upregulation in solid tumors (112,134,135).

Targeted delivery focuses on nanocarriers. Liposomes increase drug concentration in osteosarcoma by 8-fold via the enhanced permeability and retention effect (136,137). Epidermal growth factor receptor (EGFR)-targeted polymeric nanocarriers cross the blood-brain barrier, boosting drug concentration in glioma brains by 12-fold (74,138). Inorganic nanocarriers combined with photothermal effects achieve a 55% ORR in breast cancer (135,139). Liver-specific carriers enhance intrahepatic drug concentration in HCC by 6-fold (140,141).

Combination strategies rely on mechanistic synergy. In epigenetic combinations, HDACis plus DNMTis increase ORR from 30 to 60% in AML (36,142). In immune combinations, HDACis plus anti-PD-1 antibodies raise ORR from 25 to 50% in melanoma (143,144). In targeted combinations, HDACis plus PI3K inhibitors improve ORR from 20 to 45% in patients with ovarian cancer who exhibit PI3K pathway activation (58,145).

The development of HDAC isoform-selective inhibitors represents a novel research direction in cancer therapy. As core molecules in epigenetic regulation, HDACs modulate key cellular processes through deacetylation. Notably, different HDAC isoforms exhibit distinct expression patterns and functions across tumors. For instance, the upregulation of class I HDACs in TNBC is associated with poor prognosis and therapeutic resistance, making them a precise target for intervention. This therapeutic approach not only enhances efficacy but also avoids the off-target effects commonly observed with pan-HDACis (146).

The mechanisms underlying acquired resistance to HDACis are complex, such as the compensatory upregulation of alternative HDAC isoforms in AML (125). Researchers are accelerating the development of novel drugs through various strategies, including combining HDACis with chemotherapy/targeted agents, dynamically adjusting treatment regimens via biomarker monitoring and structure-based drug design or dual-target inhibitors. Additionally, multi-target compounds provide a novel pathway in preventing drug resistance (145,147).

To advance clinical translation, three key research areas should be prioritized over the next 3–5 years: i) Developing HDAC11-selective inhibitors by using structural biology to characterize its active site, addressing sorafenib resistance in HCC and reducing off-target toxicity; ii) establishing patient stratification models based on HDAC isoform expression profiles; for example, designing screening protocols for populations with high class I HDAC expression in TNBC, constructing a multi-dimensional classification system and developing convenient detection kits; and iii) exploring interactions between HDAC isoforms and non-coding RNAs, analyzing key mechanisms such as the miR-145-5p/HDAC11 axis and identifying novel therapeutic targets and candidate biomarkers. These efforts will improve the therapeutic system from three different perspectives.

The oncology field has increasingly prioritized combinatorial regimens involving HDACis, DNMTis and histone methyltransferase inhibitors (HMTis). This multifaceted approach involves synergistic targeting of interconnected epigenetic pathways driving tumorigenesis. Preclinical evidence demonstrates that co-administration of HDACis with DNMTis achieves coordinated reversal of aberrant epigenetic silencing, reactivating tumor suppressor genes frequently muted in malignancies (36,148). When these epigenetic modifiers are combinatorially inhibited, the tumor microenvironment undergoes notable alterations. This not only enhances the antitumor immune response of the body (preclinical studies have confirmed that HDACis combined with immunotherapy can increase the immunogenicity of tumor cells) but also further improves the therapeutic efficacy of immune checkpoint inhibitors (89,149,150). Mechanistically, this multi-drug combination strategy can simultaneously block multiple aberrantly activated oncogenic signaling pathways, among which the PI3K/AKT and NF-κB pathways are the most representative targets (151). Incorporating HMTis into combination frameworks amplifies therapeutic impact through layered epigenetic reprogramming. Dual modulation of histone acetylation and methylation status enables comprehensive restoration of silenced tumor suppressor networks key to apoptosis induction (35,152,153). This multitarget strategy overcomes limitations inherent to monotherapy by exploiting synergistic interactions across parallel epigenetic regulatory axes (154). Ongoing clinical trials systematically evaluate diverse combinations with conventional chemotherapy and novel agents, aiming to maximize efficacy while minimizing chemotoxicities associated with traditional cytotoxic regimens (155–159). The integration of multimodal epigenetic therapies represents a paradigm shift towards precision medicine in cancer treatment.

HDACs are key regulators of the TIME. By epigenetically modifying immune regulatory genes, HDACs modulate the dynamics of immune cells and facilitate tumor immune evasion. Elevated HDAC activity reduces the infiltration of effector cells such as natural killer and CD8⁺ T cells, thereby establishing an immunosuppressive microenvironment (12,38,160). Dysregulated HDAC function further exacerbates immune evasion by inhibiting tumor suppressor pathways and upregulating molecules such as programmed cell death-ligand 1 (143,161). For instance, in pancreatic adenocarcinoma, upregulated HDACs impede T cell-mediated antitumor immune responses and recruit MDSCs to form an immune barrier (126).

HDAC-targeted therapy has notable immunomodulatory potential. Combining HDACis with immune checkpoint blockade therapy can reverse immunosuppression (151,162). At the molecular level, HDAC inhibition increases the expression levels of major histocompatibility complex class I molecules on tumor cells and enhances the activity of key components in the antigen-processing system, thus improving T-cell recognition efficiency (2,44). It also reprograms tumor-associated macrophages from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype, thus weakening the ability of the tumor to evade immunity (149,163).

Additionally, HDACs regulate the function of regulatory T cells (Tregs) by interacting with forkhead box protein P3 (FOXP3) regulators. For example, HDAC3 forms a complex with FOXP3 negative regulators to inhibit FOXP3 activity, while HDACis disrupt this complex to relieve the inhibition, reducing Treg-mediated immunosuppression and enhancing the cytotoxicity of effector T cells. The identification of the HDAC-FOXP3-Treg axis provides a theoretical basis for the combination of HDAC-targeted therapy with immunotherapy (164).

Currently, the research and development of novel HDACis focuses on enhancing subtype selectivity, reducing toxicity and overcoming drug resistance, driven by interdisciplinary technologies. By resolving the active pocket structures of HDAC subtypes using X-ray crystallography and cryo-electron microscopy, combined with high-throughput screening, candidate molecules can be rapidly identified. For instance, tetrapheno(α)3-methyl derivatives exhibit nanomolar-level inhibitory activity against HDAC1/6 and demonstrate antiproliferative effects in various cancer cell lines (165,166). Using molecular docking and molecular dynamics simulations to optimize compound structures, dual-target drugs such as 4-arylaminoquinoline derivatives have also been developed, which can simultaneously target the HDAC and EGFR pathways (124,167,168). Additionally, PROTACs technology has emerged as a novel direction; for example, HDAC7 PROTAC degraders can specifically degrade HDAC7 in DLBCL, with antitumor activity >10-fold higher compared with that of traditional inhibitors and low toxicity to normal cells (169).

Preclinical evaluation of novel HDACis requires multi-dimensional validation across the molecular-cell-animal spectrum. At the molecular level, the selectivity for target subtypes is verified; at the cellular level, the effects on drug-resistant strains and other cell types are assessed; and at the animal level, in situ xenograft models are used to monitor efficacy and drug distribution. Meanwhile, toxicity to systems such as the hematological, digestive and nervous systems is closely monitored as well. Pharmacokinetic-pharmacodynamic models are employed to optimize dosing regimens or targeted delivery technologies are used to increase drug concentrations in tumor tissues and reduce systemic toxicity. For clinical trials, cancer types and patient groups are selected based on the properties of the drug. For example, HDAC11 inhibitors are first investigated in HCC (113–116), while dual-target drugs are administered to patients with pathway abnormalities (58,124,167,168). In combination therapy trials, relevant molecular markers need to be monitored (37,56,57,100). Although challenges exist, such as the lack of structural data for certain HDAC subtypes and the difficulty of preclinical models in simulating tumor heterogeneity, these can be addressed through homology modeling and patient-derived xenograft models. In the future, integrating biomarker stratification should facilitate the advancement of more HDACis with high efficacy and low toxicity into clinical practice. The key results of recent clinical trials of therapeutic regimens based on histone deacetylase inhibitors are summarized in Table I.