HDAC11 (Histone Deacetylase 11)

In breast cancer models, elevated RAD51 succinylation correlates with reduced HR capacity and increased sensitivity to the PARP inhibitor olaparib, whereas diminished succinylation confers resistance. Moreover, a cell-penetrating peptide that disrupts the RAD51-HDAC11 interaction increases RAD51 succinylation and synergizes with chemotherapy. Collectively, our findings uncover a metabolic-epigenetic mechanism linking protein succinylation to HR and genomic stability and identify RAD51 succinylation as a predictive biomarker and therapeutic target in cancer.

Moreover, nanoparticles encapsulating both HDAC11 and TGF-β1 inhibitors effectively suppressed HCC cell proliferation and metastasis. This research elucidates the molecular mechanism by which HDAC11 inhibits metastasis and provides an effective strategy to mitigate the side effects associated with HDAC11 inhibition, offering novel insights and approaches for the precision treatment of HCC.

This study highlights the need for rigorous validation of results. In our case, two orthogonal testing methods were not sufficient to catch all the confounding factors involved in measurement of HDAC inhibition, and a third approach was required to identify the actual inhibition of 9 against HDAC9 and 11.

Proteomics revealed 64 putative substrates, with follow-up studies documenting that HDAC11 deacetylates the BRAF kinase on K680 to suppress kinase activity and cell proliferation. Given the established role of BRAF in cancer, HDAC11-mediated deacetylation likely influences signaling pathways in tumor progression, underscoring the diverse regulatory role of HDAC11 in cellular events.

Here, we report that TPI1 expression was elevated in IPF tissues and in mice with bleomycin-induced pulmonary fibrosis...Notably, we designed and tested the activity of a novel cell-penetrating peptide that increased the acetylation of TPI1 and markedly promoted TPI1 degradation, thereby effectively reducing fibrosis. Together, our findings revealed that targeting TPI1 acetylation is an effective strategy for IPF therapy, and the specific cell-penetrating peptide could prevent IPF by promoting the acetylation of TPI1.

Both compounds are drug-like and exhibit favorable physicochemical and pharmacokinetic profiles, particularly beneficial water solubility and good adsorption, making them valuable starting points for further optimization. These findings open new avenues for the development of selective, non-hydroxamate HDAC11 inhibitors with potential therapeutic applications.

qRT-PCR also confirmed the downregulation of GM11266, a long non-coding RNA, in HDAC11-overexpressing CMSCs. In summary, HDAC11 overexpression promotes transcriptional reprogramming, cell cycle progression, and CMSC proliferation, underscoring its potential role in regulating CMSC growth and division.

These findings indicate that HDAC11 is crucial for renal fibrosis development by promoting pEMT and G2/M phase cell cycle arrest in renal epithelial cells through multiple profibrotic signaling pathways. Therefore, targeting HDAC11 may be a promising therapeutic strategy to alleviate renal fibrosis.

Molecular docking and MD simulations further provide an in-depth analysis of the binding interaction of the identified fingerprints in the catalytic site of HDAC11. In brief, our study delivers some important structural attributes that will aid medicinal chemists in designing and developing future potent HDAC11 inhibitors.

The robust in vivo anti-AML efficacy of A9, alone and combined with cytarabine, was also validated. Collectively, our study revealed pharmacological inhibition of HDAC11 as a potential therapeutic strategy for AML.

Using statistical modeling, we inferred that the interaction between OIP5-AS1 and HDAC proteins, especially HDAC11, is associated with tau tangles in excitatory neurons and plaque burden in microglia. Our study represents a valuable resource of lncRNA spatial expression in the aged human brain, shedding mechanistic insights into their functional roles in AD and neurodegeneration.