HDAC11

The prevalence of metabolic diseases is increasing at a frightening rate year by year. The burgeoning development of deep learning enables drug design to be more efficient, selective, and structurally novel. The critical relevance of Histone deacetylase 11 (HDAC11) to the pathogenesis of several metabolic diseases makes it a promising drug target for curbing metabolic disorders. The present study aims to design new specific HDAC11 inhibitors for the treatment of metabolic diseases. Deep learning was performed to learn the properties of existing HDAC11 inhibitors and yield a novel compound library containing 23,122 molecules. Subsequently, the compound library was screened by ADMET properties, Lipinski & Veber rules, traditional machine classification models, and molecular docking, and 10 compounds were screened as candidate HDAC11 inhibitors. The stability of the 10 new molecules was further evaluated by deploying RMSD, RMSF, MM/GBSA, free energy landscape mapping, and PCA analysis in molecular dynamics simulations. As a result, ten compounds, Cpd_17556, Cpd_2184, Cpd_8907, Cpd_7771, Cpd_14959, Cpd_7108, Cpd_12383, Cpd_13153, Cpd_14500and Cpd_21811, were characterized as good HDAC11 inhibitors and are expected to be promising drug candidates for metabolic disorders, and further in vitro, in vivo and clinical trials to demonstrate in the future.

The N6-methyladenosine (m⁶A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the m⁶A demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the Alkbh5 promoter and promoting Alkbh5 transcription. The increased ALKBH5 erases m⁶A sites in Htr3a messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to Htr3a mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury-induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through m⁶A-dependent stabilization of Htr3a mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.

Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the relationship with disease susceptibility remains unclear. In this study, we find sex-differential changes in the gut microbiota of 6-month-old infants with prenatal dexamethasone therapy (PDT) that persisted in female infants up to 2.5 years of age with altered bile acid metabolism. PDE female offspring rats show abnormal colonization and composition of gut microbiota and increased susceptibility to cholestatic liver injury. The aberrant gut microbiota colonization in the PDE offspring can be attributed to the inhibited Muc2 expression caused by decreased CDX2 expression before and after birth. Integrating animal and cell experiments, we further confirm that dexamethasone could inhibit Muc2 expression by activating GR/HDAC11 signaling and regulating CDX2 epigenetic modification. This study interprets abnormal gut microbiota and disease susceptibility in PDT offspring from intrauterine intestinal dysplasia.