Phytic acid (InsP6) activates HDAC3 epigenetic axis to maintain intestinal barrier function

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.