Phytic Acid (InsP 6 ) Activates HDAC3 Epigenetic Axis to Maintain Intestinal Barrier Function
Open accessPreprint — published as 10.1038/s41467-026-68994-0
Abstract
While HDAC inhibition shows promise in cancer treatment, pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treat diverse diseases beyond cancer. Our study reveals the essential role of inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP 6 or phytic acid), enriched in vegan diets, in activating the HDAC3 epigenetic axis and maintaining intestinal barrier integrity. IPMK binds to HDAC3, driving InsP 6 synthesis, which selectively activates HDAC3 at 10nM concentration by recruiting the DAD domain of its corepressor protein. IPMK deletion diminishes HDAC3 activation, leading to histone hyperacetylation and MMP gene transcription, compromising intestinal barrier integrity. InsP 6 treatment is sufficient to rescue these effects. In inflammatory bowel disease, diminished IPMK levels exacerbated intestinal permeability, while oral InsP 6 treatment mitigated gut permeability by restoring the HDAC3 epigenetic axis, indicating the clinical implications of the IPMK-HDAC3 epigenetic axis and therapeutic potential of phytic acid.
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Depletion of IPMK in cells or mouse tissue significantly diminishes HDAC3 activation and results in increased histone acetylation.
“Recent research has shown that depletion of IPMK—responsible for synthesizing HOIPs—in cells or mouse tissue significantly diminishes HDAC3 activation and results in increased histone acetylation [78,79].”
From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [78]
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From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease
Mishra, S. H., Chatterjee, S., Viera-Preval, L., & Guha, P. (2025) · Biomolecules · doi:10.3390/biom15091266 · Cited by 1 · see citing works
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- Authors
- Chetterjee, S., Sin, Z., Tran, N., Vierra, L., Shukla, A., Tran, T., Koshkaryan, G., Ritter, K., Su, X. B., Ragsac, S. J., Park, S., Liu, Q., Van, R., Han, M., Saiardi, A., Huang, K., Huff-Hardy, K., Rood, R., Gremida, A., Gregory, M., Chen, C.-H., Deepak, P., Jessen, H. J., & Guha, P.
- Affiliations
- University of Nevada, Las Vegas (US)
- University of Freiburg (DE)
- MRC Laboratory for Molecular Cell Biology (GB)
- Washington University in St. Louis (US)
- Corresponding author
- Guha, Prasun
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2024-09-16
- Volume
- 17
- Issue
- 1
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11429887
- OpenAlex
- W7128429619
- Cited by
- 9
- References
- 0
- Citations by year
- 2026: 5 · 2025: 4
- FWCI
- 10.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.biorxiv.org/about/FAQ#license (vor)
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion)
- Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- NIH
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytase and its Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- phytic acid, HDAC3, inositol polyphosphate multikinase, intestinal barrier function, histone hyperacetylation, corepressors, leaky gut, intestinal permeability, inflammatory bowel disease, vegan diet, epigenetic regulation
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