A conformation-sensitive product inhibitor of HDAC1/2 potentiates WNT signaling.

WNA1, an isoxazole-based small molecule, selectively inhibits complex-bound HDAC1/2 and potentiates WNT/β-catenin signaling, promoting skin hair growth in vivo.

• Why it matters: Enhancing WNT/β-catenin signaling could support tissue repair and regeneration, but existing HDAC inhibitors show limited β-catenin stabilization, leaving a mechanistic gap.
• What they did: The authors tested WNA1 in WNT-dependent β-catenin assays and in vivo for hair growth, then used histone acetylation measurements, HDAC1/2 NuRD studies, and structural/biochemical analyses to define a foot-pocket product-inhibition mechanism.
• The result: WNA1 increases histone acetylation with minimal activity on uncomplexed recombinant HDACs, represses β-catenin via NuRD, and enhances β-catenin by selectively inhibiting HDAC1/2 through an inositol-hexaphosphate-dependent, foot-pocket-trapped product.

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