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.
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Data availability
The RNA-sequencing data generated in this study have been deposited in the SRA database under accession code PRJNA1354901. Source data are provided with this paper.
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Acknowledgements
This work was supported by NIH R16GM154726 and 5P20GM121325 COBRE grant and University of Nevada, Las Vegas start-up funds to Prasun Guha. This work was supported by UK Research and Innovation (UKRI)’s Medical Research Council (MRC) grant MR/T028904/1. The partial publication fee covered by GM103440. We would like to thank NIPM’s Genomic Core for assisting with instruments and experiments. The specimen collection and phenotyping were made possible by the Washington University (WU) DDRCC (NIDDK P30 DK052574). Parakkal Deepak was supported by the Helmsley Charitable Trust, the IBD Plexus of the Crohn’s and Colitis Foundation, and the Leo & Carean Goss Crohn’s Disease Research Fund. The publication fees for this article were supported by the UNLV University Libraries Open Article Fund. We would like to thank Marc C Jhonson, from University of Missouri-School of Medicine for generously providing IPPK Knock out cells. We would like to thank Mark Donowitz from Johns Hopkins Medicine, Mark Donowitz from Johns Hopkins Subrata H Mishra from NIST and Brian Hedlund from UNLV for reading and editing the paper and giving suggestions.
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P.G. conceived the study. P.G. and S.C. designed the experiments. S.C. performed most experiments. Z.S. and L.V.P. validated major biochemical experiments. S.C. performed wet-lab experiments related to NGS studies. Z.S., R.V. and L.V.P. performed most of the NGS data analysis. K.R. and H.J.J. generated the cell-permeable InsP6. X.B.S. and A.S. analyzed intercellular inositol content. N.T. and S.C. performed animal and microscopy related experiments. T.T. and S.C. performed IHC and microscopy data analysis. S.C. and G.K. performed microscopy and Immunoprecipitation study. K.H., K.H.H., R.R., A.G., M.G., C.H.C., P.D. provided and analyzed Human patient samples. Q.L. and M.V.H. performed NGS data validation. S.J.R., S.C. and N.T. maintained animal colonies and isolated animal samples for genotyping. S.P. performed mathematical analysis of transwell assay. S.C., Z.S. and R.V. designed the Figures. P.G. and S.C. wrote the manuscript takes responsibility of all wet lab data.
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Parakkal Deepak, MBBS MS has received research support under a sponsored research agreement unrelated to the data in the study and/or consulting from Johnson and Johnson, Pfizer, AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, CorEvitas LLC, Sandoz, Takeda Pharmaceuticals, Direct Biologics, Prometheus Biosciences, Lilly, Teva Pharmaceuticals, Merck, ExeGI Pharmaceuticals, AGMB, Landos Pharmaceuticals, Tr1X, and Boehringer Ingelheim. The remaining authors declare no conflict of interest.
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Chatterjee, S., Sin, Z., Tran, N. et al. Phytic acid (InsP6) activates HDAC3 epigenetic axis to maintain intestinal barrier function. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68994-0
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DOI: https://doi.org/10.1038/s41467-026-68994-0
