Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs h Show more
Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer. Wnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were examined in patient-specific iPSC-derived neurons and cerebral organoids carrying We herein report that CI-994 is not only a potent class I HDAC inhibitor but also an activator of Wnt/β-catenin signaling. Mechanistically, activation of Wnt/β-catenin signaling by CI-994 is associated with stabilizing Wnt co-receptor LRP6 protein and modulating HDAC activity. Importantly, CI-994 significantly increases histone acetylation, activates Wnt/β-catenin signaling, and decreases tau phosphorylation in patient-specific iPSC-derived cerebral organoids carrying Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy. The online version contains supplementary material available at 10.1186/s13195-026-01982-0. Show less