Phytic Acid (Insp6) Activates Hdac3 Epigenetic Axis to Maintain Intestinal Barrier Function

Authors

• Sujan Chatterjee, University of Nevada, Las Vegas
• Zachery Sin, University of Nevada, Las Vegas
• Nguyen Tran, University of Nevada, Las Vegas
• Loretta Vierra, University of Nevada, Las Vegas
• Anuj Shukla, University of Freiburg
• Tam Tran, University of Nevada, Las Vegas
• George Koshkaryan, University of Nevada, Las Vegas
• Kevin Ritter, University of Freiberg
• Xue Bessie Sue, University College London
• Saharat Jolak Ragsac, University of Nevada, Las Vegas
• Seungman Park, University of Nevada, Las Vegas
• Qian Liu, University of Nevada, Las Vegas
• Richard Van, University of Nevada, Las Vegas
• Katherine Huang, Washington University School of Medicine in St. Louis
• Kayci Huff-Hardy, Washington University School of Medicine in St. Louis
• Richard Rood, Washington University School of Medicine in St. Louis
• Anas Gremida, Washington University School of Medicine in St. Louis
• Martin Gregory, Washington University School of Medicine in St. Louis
• Chien-Huan Chen, Washington University School of Medicine in St. Louis
• Mira V. Han, University of Nevada, Las Vegas
• Parakkal Deepak, Washington University School of Medicine in St. Louis
• Adikfi Saiardi, University College London
• Henning J. Jensen, University of Freiburg
• Prasun Guha, University of Nevada, Las Vegas

Document Type

Article

Publication Date

2-9-2026

Publication Title

Nature Communications

Volume

17

First page number:

1

Last page number:

84

Abstract

HDAC inhibition shows promise in cancer treatment but pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treating diverse diseases beyond cancer. Our study reveals that inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP6 or phytic acid), enriched in vegan diets, play essential roles in activating the HDAC3 epigenetic axis and maintaining intestinal barrier integrity. IPMK binds to HDAC3 and drives InsP6 synthesis, which selectively activates HDAC3 at a 10 nM concentration by recruiting the DAD domain of its corepressor protein. IPMK deletion diminishes HDAC3 activation, leading to histone hyperacetylation and MMP gene transcription that compromise intestinal barrier integrity. InsP6 treatment is sufficient to rescue these effects. In inflammatory bowel disease, diminished IPMK levels exacerbate intestinal permeability, while oral InsP6 treatment mitigates leaky gut effects by restoring the HDAC3 epigenetic axis, highlighting the clinical significance of the IPMK-HDAC3 pathway and the therapeutic potential of phytic acid.

Controlled Subject

Cancer--Treatment; Gastrointestinal system--Diseases--Treatment; Enzymes

Disciplines

Enzymes and Coenzymes | Neoplasms

File Format

PDF

File Size

26300 KB

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Repository Citation

Chatterjee, S., Sin, Z., Tran, N., Vierra, L., Shukla, A., Tran, T., Koshkaryan, G., Ritter, K., Sue, X. B., Ragsac, S. J., Park, S., Liu, Q., Van, R., Huang, K., Huff-Hardy, K., Rood, R., Gremida, A., Gregory, M., Chen, C., Han, M. V., Deepak, P., Saiardi, A., Jensen, H. J., Guha, P. (2026). Phytic Acid (Insp6) Activates Hdac3 Epigenetic Axis to Maintain Intestinal Barrier Function. Nature Communications, 17 1-84.
http://dx.doi.org/10.1038/s41467-026-68994-0