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.

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/Objectives: Fatty acids (FAs) play crucial roles in human physiology, and their levels have been associated with hypertension, although with inconsistent findings. Primary Aldosteronism (PA), a common, often underdiagnosed form of secondary hypertension, carries a higher risk of organ damage compared to essential hypertension (EH). This study aimed to compare plasma FA profiles of patients with unilateral PA and EH and explore the impact of therapies. Methods: Participants were recruited at the Hypertension Unit of Verona University Hospital. PA diagnosis/subtype was confirmed according to guidelines. Blood samples were collected at enrollment and at follow-up (after treatment with a mineralocorticoid receptor antagonist (MRA) and adrenalectomy). Plasma long- and very-long-chain FAs were extracted and analyzed using gas chromatography. Results: Each sample was assessed for a panel of 19 selected FA species. Compared to EH (n = 60), PA patients (n = 22) exhibited lower plasma levels of behenic acid (p = 0.03), total monounsaturated fatty acids (p = 0.02), specifically palmitoleic (p = 0.005) and erucic acids (p = 0.02), and higher levels of ω6 polyunsaturated fatty acids (PUFAs, p = 0.02). Longitudinal analysis in PA patients showed that MRAs decreased total saturated FAs (p_ADJ = 0.01) and increased total PUFAs (p_ADJ = 0.006), and these changes were largely maintained even after adrenalectomy. Conclusions: This pilot study reveals significant alterations in the plasma FA profiles of PA patients compared to EH, suggesting a more prominent inflammatory state in PA. Both pharmacological and surgical interventions induced a positive shift in the FA profile of PA patients. These findings highlight the potential of FAs as biomarkers for PA risk stratification and may offer novel therapeutic opportunities.