Phytic Acid (InsP ₆ ) Activates HDAC3 Epigenetic Axis to Maintain Intestinal Barrier Function

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.