Age‐related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome‐wide association studies (GWAS) risk variants. Our research on Cryba1 , encoding βA3/A1‐crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1 ‐depleted cells likely diminishes the HDAC3‐DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1 ‐deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age‐dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD‐linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene‐agnostic and epigenetic therapeutic strategies for treating AMD.

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.

Once a protein of relative obscurity, inositol polyphosphate multikinase (IPMK) emerged as a versatile and indispensable enzyme in cellular biology. With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms. Initially identified in yeast and later recognized as essential for mammalian embryonic development, IPMK has transitioned from a niche interest to a focal point in studies of nutrient sensing, growth factor signaling, mRNA transport, and transcription regulation. Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation. This review charts IPMK’s journey from obscurity to prominence, examining its structure–function relationships, cellular roles, and emerging physiological impacts, while highlighting its potential as a therapeutic target in human health and disease.