GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328958/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328958GEOGSEfalseA conformation-sensitive product inhibitor of HDAC1/2 potentiates WNT/β-catenin signaling [ChIP-seq]Pharmacological enhancement of WNT/β-catenin signaling holds promises for tissue repair and regeneration. Here, we identify WNA1, an isoxazole-based small molecule, as a potent activator of WNT/β-catenin signaling. WNA1 stimulates β-catenin signaling in different cellular contexts, and this activity requires production of endogenous WNT. In vivo, WNA1 promotes skin hair growth, consistent with the established role of β-catenin signaling in hair follicle development. Intriguingly, WNA1 increases histone acetylation with minimal activity on uncomplexed recombinant histone deacetylases (HDACs), while conventional HDAC inhibitors exhibit minimal β-catenin-stabilizing activity. We demonstrate that β-catenin signaling is repressed by the HDAC1/2-containing NuRD complex, and that WNA1 enhances β-catenin signaling through selectively inhibiting HDAC1/2. Structural and biochemical analyses reveal that WNA1 is hydrolyzed by the HDAC1-MTA1 complex, and its product is trapped in the foot-pocket of HDAC1 in an InsP6-dependent manner. HDAC1 mutants with reduced foot-pocket abrogate WNA1-induced histone acetylation and β-catenin accumulation. These findings establish WNA1 as a conformation-sensitive, foot-pocket-anchored product inhibitor that selectively targets complex-bound HDAC1/2. Our study reveals a unique mechanism for HDAC1/2 inhibition and WNT potentiation, paving the way for therapeutic applications.2026/09/01GSE328958GSM9694879GSM9694878GSM9694886GSM9694885GSM9694888GSM9694887GSM9694882GSM9694881GSM9694884GSM9694883GSM9694880GSM9694889GSM9694869GSM9694875GSM9694874GSM9694896GSM9694877GSM9694876GSM9694871GSM9694893GSM9694892GSM9694870GSM9694895GSM9694873GSM9694894GSM9694872GSM9694891GSM969489016791328958Homo sapiens