Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget‐directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress‐related conditions. We herein report the design, synthesis, and biological evaluation of the first‐in‐class FAAH‐HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1‐phenylpyrrole‐based compounds 4a–j. The best‐performing compounds (4c, 4f, and 4h) were tested for their neuroprotective properties in oxidative stress models, employing 1321N1 human astrocytoma cells and SHSY5 human neuronal cells. In our preliminary studies, compound 4h stood out, showing a balanced nanomolar inhibitory activity against the selected targets and outperforming the standard antioxidant N‐acetylcysteine in vitro. Together with 4f, 4h was also able to protect 1321N1 cells from tert‐butyl hydroperoxide or glutamate insult. Our study may provide the basis for the development of novel MTDLs targeting the ECS and epigenetic enzymes.

Walnuts (Juglans regia L.) are recognized for their rich nutritional profile and health-promoting properties. This study investigates the impact of biostimulation, via wood distillate application, on the chemical composition and therapeutic potential of walnut kernels, focusing on their wound healing activity. Biostimulated walnuts showed enhanced levels of phenolic compounds including antioxidants, sugars, and amino acids compared to untreated or agrochemically treated controls. Phytocomplexes extracted from walnut kernels using green methodologies were tested on human keratinocytes (HaCaT), revealing pro-migratory effect, boosted by biostimulation. Molecular analyses demonstrated the activation of epithelial–mesenchymal transition (EMT) pathways, marked by downregulation of epithelial markers and upregulation of mesenchymal genes such as MMP3, MMP9, vimentin, and SMAD3. Furthermore, a synergistic effect was observed between extracts derived from biostimulated kernels and manuka honey in promoting wound closure. These findings suggest that kernels from biostimulated walnuts may serve as functional foods, paving the way for their use in regenerative medicine.