Histone deacetylase 3 (HDAC3) has emerged as a critical epigenetic regulator in tumor progression and immune modulation, positioning it as a promising target for enhancing cancer immunotherapy. This work comprehensively explores HDAC3’s multifaceted roles, focusing on its regulation of key immune-modulatory pathways such as cGAS-STING, ferroptosis, and the Nrf2/HO-1 axis. These pathways are central to tumor immune evasion, antigen presentation, and immune cell activation. Additionally, the distinct effects of HDAC3 on various immune cell types—including its role in enhancing T cell activation, restoring NK cell cytotoxicity, promoting dendritic cell maturation, and modulating macrophage polarization—are thoroughly examined. These findings underscore HDAC3’s capacity to reshape the tumor immune microenvironment, converting immunologically “cold tumors” into “hot tumors” and thereby increasing their responsiveness to immunotherapy. The therapeutic potential of HDAC3 inhibitors is highlighted, both as standalone agents and in combination with immune checkpoint inhibitors, to overcome resistance and improve treatment efficacy. Innovative strategies, such as the development of selective HDAC3 inhibitors, advanced nano-delivery systems, and integration with photodynamic or photothermal therapies, are proposed to enhance treatment precision and minimize toxicity. By addressing challenges such as toxicity, patient heterogeneity, and resistance mechanisms, this study provides a forward-looking perspective on the clinical application of HDAC3 inhibitors. It highlights its significant potential in personalized cancer immunotherapy, paving the way for more effective treatments and improved outcomes for cancer patients.

Background: Sini decoction (SND), a popular formula from traditional Chinese medicine (TCM), plays a critical role in the treatment of liver disease. Its protective effect for the heart against cardiovascular diseases is well documented. However, its effects and pharmacological mechanisms for the liver remain unclear. This study aimed to clarify the effect and mechanism of the SND-polysaccharide compound (SNDPC) on hepatocellular carcinoma (HCC). Methods: Different genes affected by SNDPC in HCC were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Databases including Multi-Experiment Matrix (MEM), HCCDB, LinkedOmics, and Gene Expression Profiling Interactive Analysis (GEPIA) were used to determine the correlation between PHLDA2 and ANXA2. Cell proliferation and viability were identified using Cell Counting Kit-8 (CCK-8). Cell apoptosis was estimated using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and Western blotting. Glycolysis was determined by measuring glucose uptake, lactate concentration, extracellular acidification rate (ECAR), and the expressions of LHDA, HK2, and PKM2. The binding between PHLDA2 and ANXA2 was identified by coimmunoprecipitation. Results: SNDPC significantly weakened cell proliferation, facilitated cell apoptosis, and suppressed glycolysis by reducing glucose uptake, lactate concentration, ECAR, and the expressions of LDHA, HK2, and PKM2 in HCC cells. Furthermore, PHLDA2 was predicted to bind to ANXA2, which was confirmed by coimmunoprecipitation. SNDPC reduced the expressions of PHLDA2 and ANXA2 in HCCLM3 cells, and PHLDA2 silencing decreased the proliferation of cells, promoted cell apoptosis, and inhibited glycolysis of HCCLM3 cells while reversing the overexpression of PHLDA2. Conclusions: SNDPC suppressed proliferation and glycolysis while accelerating the apoptosis of HCC cells through PHLDA2/ANXA2.

A neutral glucan, GJ0D, was obtained from dried ginger (Zingiberis rhizoma) by enzymatic extraction and purification with column chromatography. The fine structure of GJ0D was assessed through monosaccharide composition analysis, methylation, and two-dimensional nuclear magnetic resonance. GJ0D has a relative molecular weight of 4.0 KDa and possesses a backbone consisting of 1,4-linked α-Glcp with substitution at C-6 of Glcp by T-Glcp. Immunoactivity assessment showed that GJ0D significantly upregulates the expression of IL-6, IL-1β, and TNF-α in RAW264.7 cells. The reactive oxygen species (ROS) production was also increased in RAW264.7 cells. In addition, the expression of several proteins associated with immune activation signaling pathways including TLR4, the phosphorylation of IKKβ, and NF-κB (p100 and p52) were significantly upregulated by GJ0D. These results suggest that GJ0D could promote inflammation through the TLR4/IKKβ/P100 signaling pathway, suggesting a potential application as an immunomodulating agent.

Angiogenesis is crucial for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and Notch ligand Delta-like 4 (Dll4) play a critical role in vessel formation and angiogenesis. This study aimed to determine anti-angiogenesis effects of Sini Decoction serum on human umbilical vein endothelial cells (HUVECs). We prepared Sini Decoction serum in doses of 0.925, 1.85, 3.7 g/mL, and administered to HUVECs. HUVECs migration was evaluated using a wound healing assay. Formation of tube-like structures in HUVECs was observed using a tube-formation assay. Gene transcriptions of Dll4, Notch1, VEGF receptor 2 (VEGFR-2) and VEGF were examined using a PCR assay. Protein expressions of Janus kinase-2/signal transducer and activator of transcription 3 (JAK2/STAT3) molecules and signal molecules downstream of VEGF/VEGFR related to angiogenesis (including mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase-1/2 (ERK1/2), focal adhesion kinase (FAK) and phosphorylated protein kinase B (p-Akt)) were detected by western blot. Sini Decoction serum significantly inhibited cell migration and the formation of tube-shaped structures in HUVECs compared to Control group (P<0.05). Sini Decoction serum markedly decreased Dll4, Notch1, VEGF, and increased VEGFR-2 gene transcriptions, compared to those of Control group (P<0.05). Sini Decoction serum significantly reduced expression of p-Akt, p38MAPK and ERK1/2, compared to Control group (P0.05). In conclusion, Sini Decoction serum modulated the expression of angiogenesis-associated molecules in HUVECs by activating VEGF-Dll4/Notch1 and p38MAPK/ERK1/2/p-AKT signalling pathways.