Sujan Chatterjee, Zachary Sin, Nguyen H. Tran, Loretta Vierra, Anuj Shukla, Tam Tran, George Koshkaryan, Kevin Ritter, Xue Bessie Su, Saharat Jolak Ragsac, Seungman Park, Qian Liu, Richard Van, K Huang, Kayci Huff-Hardy, Richard P. Rood, Anas Gremida, Gregory Mh, Chien-Huan Chen, Mira V. Han, Parakkal Deepak, Adolfo Saiardi, Henning J. Jessen, Prasun Guha
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. The study finds that IPMK and InsP6activate HDAC3 to preserve gut integrity. Loss of IPMK impairs this axis, causing leaky gut, while InsP6 restores HDAC3 function, offering a potential therapy for inflammatory bowel disease.