Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality worldwide. Increasing evidence indicates that epigenetic mechanisms, which are potentially reversible and modifiable by environmental and nutritional factors, play a key role in hepatocarcinogenesis. Histone deacetylases (HDACs) are fundamental epigenetic modulators that regulate chromatin dynamics and ultimately gene transcription with important pathophysiological implications and promising therapeutic perspectives. The role of HDACs is gaining interest for the understanding of HCC development mechanisms and for the potential therapeutic implications of their natural and synthetic inhibitors. This review provides an overview on HDACs classification and their peculiar expression patterns in HCC, with a focus on zinc-dependent histone deacetylases (HDACs). HDAC inhibitors (HDACis), both synthetic and natural-derived compounds, are also discussed for their emerging effects in optimizing the anticancer efficacy of the current therapeutic strategies. Novel dietary-derived and bioactive compounds-based interventions are discussed in the context of HCC management as promising nutri-epigenetic avenues. Targeting HDACs bears a significant therapeutic potential for HCC management while further confirmatory clinical investigation is warranted.

Asthma is a complex, multifactorial inflammatory disorder of the airways, characterized by recurrent symptoms and variable airflow obstruction. So far, two main asthma endotypes have been identified, type 2 (T2)-high or T2-low, based on the underlying immunological mechanisms. Recently, extracellular vesicles (EVs), particularly exosomes, have gained increasing attention due to their pivotal role in intercellular communication and distal signaling modulation. In the context of asthma pathobiology, an increasing amount of experimental evidence suggests that EVs secreted by eosinophils, mast cells, dendritic cells, T cells, neutrophils, macrophages, and epithelial cells contribute to disease modulation. This review explores the role of EVs in profiling the molecular signatures of T2-high and T2-low asthma, offering novel perspectives on disease mechanisms and potential therapeutic targets.

Background/Objectives: The pathophysiology of cancer anorexia is multifactorial and unclear. Transcriptomic analysis from PBMCs RNA showed diverse patterns of gene expression pathways in anorexic cancer patients. We assessed whether the different transcriptomic signatures are modulated by DNA methylation in lung cancer patients presenting with poor appetite. Methods: Lung cancer patients and controls were enrolled, and anorexia was assessed by the FAACT-score questionnaire. Genome-wide DNA methylation was determined by Human Infinium MethylationEPIC BeadChip Kit. Data from genome-wide methylation analysis were merged with those from gene expression analysis, previously obtained by RNA sequencing (NGS). Four groups of genes were identified for each comparison: hypermethylated repressed, hypermethylated induced, hypomethylated repressed, and hypomethylated induced. Results: Cancer patients (n = 16) showed 382 differentially methylated genes when compared with controls (n = 8). Anorexic patients (n = 8) presented 586 hypomethylated and 174 hypermethylated genes compared with controls. In anorexic patients vs. non-anorexic (n = 8), 211 genes were identified as hypomethylated and 90 hypermethylated. When microarray methylation data were merged with transcriptomic data by RNA sequencing, we observed significant differences in anorexic patients vs. controls; a total of 42 genes resulted as hypomethylated and induced, 5 hypermethylated repressed, 10 hypermethylated induced, and 15 hypomethylated repressed. The CG sites analyzed by targeted bisulfite NGS in four genes of interest (FLNA, PGRMC1, GNL3L, and FHL1) resulting as hypomethylated in anorexic vs. controls allowed the validation of the data obtained from DNA methylation. Interestingly, the four genes resulted as hypomethylated in anorexic patients vs. non-anorexic patients and vs. controls (p < 0.0001). Conclusions: Our data support that methylation is implicated in cancer-associated anorexia and nutritional derangements among lung cancer patients.

Histone deacetylases (HDACs) and lysine demethylases (KDMs) are key epigenetic enzymes regulating chromatin structure and gene transcription. Aberrant expression of those epigenetic modifiers has been extensively documented in cancer, but their role in hepatocellular carcinoma (HCC) is yet undefined. In this study, we aimed to analyze the expression of specific components of HDACs and KDMs in the liver tissue of HCC patients and evaluate the possible association with clinical outcome. Fifty-four patients with HCC of nonviral etiology were enrolled and followed-up for clinical and biochemical parameters after curative surgery. Gene expression of HDAC11 , KDM5D , KDM6B , and KDM8 was assessed in HCC tissues and homologous non-neoplastic liver tissues by RealTime q-PCR. For a subset of patients, total HDAC enzymatic activity in nuclear extracts from liver tissues was assessed. HDAC11 was upregulated in 32 and downregulated in 19 HCC samples. In contrast, KDMs genes resulted mostly downregulated in HCC. Kaplan-Meier survival analysis revealed that patients with HDAC11 upregulation had a significantly higher mortality rate than those with HDAC11 downregulation ( p = 0.041). Furthermore, Cox regression analysis showed that HDAC11 expression was a predictor of mortality with a hazard ratio (HR) of 2.29 (95% CI, 1.01–5.22; p = 0.04). This mortality risk even increased when adjusted for age, sex, C-reactive protein, creatinine, albumin, alpha fetoprotein, lipid parameters, microvascular invasion and tumor differentiation degree. These findings highlight a possible prognostic role for HDAC11 in HCC and suggest to consider the potential of targeting histone-modifying enzymes for future therapeutic strategy.

Background: The anti-IL-5 monoclonal antibody, mepolizumab, has shown clinical efficacy and safety for the treatment of severe eosinophilic asthma (SEA), chronic rhinosinusitis with nasal polyps (CRwNP) and eosinophilic granulomatosis with polyangiitis (EGPA). We aimed to investigate the trajectories of the inflammatory cytokines at the systemic level during mepolizumab treatment, in SEA, SEA with CRwNP, and EGPA. Material and Methods: Treatment response was explored within a real-life observational prospective study. Clinical, functional and inflammatory outcomes as well as serum T2 (IL-4, IL-5 and IL-13) and non-T2 cytokine trends (including IL-5, IL-6, IL-13, IL-10) were evaluated at baseline and 6–12 months after mepolizumab initiation. Results: Overall, 45 patients were consecutively enrolled (SEA: 18; SEA with CRwNP: 9; EGPA: 18), including 27 females, with an average cohort age 60.65 years. Clinical parameters (FEV1, FeNO, SNOT 22, ACT, blood eosinophil count) improved in the different subgroups regardless of coexisting determinants of potential higher disease burden, including CRwNP and previous EGPA history. Cytokine analysis revealed heterogeneous profiles at baseline and statistically significant changes in IL-5 and IL-10 concentrations within the same disease subgroup at different time points. Conclusions: Our observations suggest the ability of mepolizumab to modulate both T2 and non-T2 immune pathways and highlight the persistence of slightly different molecular profile in different severe asthma patients depending on concomitant conditions, which is relevant for the long-term follow-up and potential association therapy combining options which address different targets. More research and larger studies are needed.