HDAC6, a class IIB HDAC isoenzyme, is unique in its structural and physiological functions. Unlike many other HDACs, it is mainly cytoplasmic. Besides histone modification, it targets non-histone proteins like Hsp90, α-tubulin, etc., and is a key regulator in various physiological and pathological conditions. It is involved in signaling pathways related to neurological disorders, cancers, rare diseases, and immunological conditions [1].

In mouse models, genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons leads to a lack of anti-obesity effect, indicating that central inhibition of HDAC6 can re-sensitize leptin signaling to induce weight loss [4]. In HFpEF mouse models, inhibiting HDAC6 with TYA-018 reverses heart failure, and male mice lacking Hdac6 gene have delayed HFpEF progression [2]. Also, HDAC6 negatively regulates DNA double-strand break repair in an enzyme-activity independent manner in cells [3].

In conclusion, HDAC6 plays crucial roles in multiple biological processes and disease conditions. Gene-knockout mouse models have revealed its significance in obesity, heart failure, and DNA repair. Targeting HDAC6 shows promise as a therapeutic strategy for various diseases, highlighting the importance of further research on its functions and inhibition mechanisms.

References:

1. Pulya, Sravani, Amin, Sk Abdul, Adhikari, Nilanjan, Jha, Tarun, Ghosh, Balaram. 2020. HDAC6 as privileged target in drug discovery: A perspective. In Pharmacological research, 163, 105274. doi:10.1016/j.phrs.2020.105274. https://pubmed.ncbi.nlm.nih.gov/33171304/

2. Ranjbarvaziri, Sara, Zeng, Aliya, Wu, Iris, Hoey, Timothy, Yang, Jin. 2024. Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice. In Nature communications, 15, 1352. doi:10.1038/s41467-024-45440-7. https://pubmed.ncbi.nlm.nih.gov/38409164/

3. Qiu, Lingyu, Xu, Wenchao, Lu, Xiaopeng, Zhang, Jun, Zhu, Wei-Guo. . The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair. In Nucleic acids research, 51, 9166-9182. doi:10.1093/nar/gkad631. https://pubmed.ncbi.nlm.nih.gov/37503842/

4. Guan, Dongxian, Men, Yuqin, Bartlett, Alexander, Mazitschek, Ralph, Ozcan, Umut. . Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss. In Cell metabolism, 36, 857-876.e10. doi:10.1016/j.cmet.2024.02.007. https://pubmed.ncbi.nlm.nih.gov/38569472/