Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK’s) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.

Recent advances in microphysiological systems (MPS), also known as organs‐on‐a‐chip (OoC), enable the recapitulation of more complex organ and tissue functions on a smaller scale in vitro. MPS therefore provide the potential to better understand human diseases and physiology. To date, numerous MPS platforms have been developed for various tissues and organs, including the heart, liver, kidney, blood vessels, muscle, and adipose tissue. However, only a few studies have explored using MPS platforms to unravel the effects of aging on human physiology and the pathogenesis of age‐related diseases. Age is one of the risk factors for many diseases, and enormous interest has been devoted to aging research. As such, a human MPS aging model could provide a more predictive tool to understand the molecular and cellular mechanisms underlying human aging and age‐related diseases. These models can also be used to evaluate preclinical drugs for age‐related diseases and translate them into clinical settings. Here, we provide a review on the application of MPS in aging research. First, we offer an overview of the molecular, cellular, and physiological changes with age in several tissues or organs. Next, we discuss previous aging models and the current state of MPS for studying human aging and age‐related conditions. Lastly, we address the limitations of current MPS and present future directions on the potential of MPS platforms for human aging research.

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.

Introductory paragraph: The retinal pigmented epithelial (RPE) cells maintain retinal homeostasis, and alterations in their function contribute to non-exudative age-related macular degeneration (AMD) ^1,2 . Here, we explore the intricate relationship between RPE cells, epigenetic modifications, and the development of AMD. Importantly, the study reveals a substantial decrease in histone deacetylase 3 (HDAC3) activity and elevated histone acetylation in the RPE of human AMD donor eyes. To investigate epigenetic mechanisms in AMD development, we used a mouse model with RPE-specific Cryba1 knockout ^3–5 , revealing that the loss of βA3/A1-crystallin selectively reduces HDAC3 activity, resulting in increased histone acetylation. βA3/A1-crystallin activates HDAC3 by facilitating its interaction with the casein kinase II (CK2) and phosphorylating HDAC3, as well as by regulating intracellular InsP6 (phytic acid) levels, required for activating HDAC3. These findings highlight a novel function of βA3/A1-crystallin as an epigenetic regulator of HDAC3 in the RPE cells and provide insights into potential therapeutic strategies in non-exudative AMD.