The Wnt–NAD+ axis in cancer, aging, and tissue regeneration
The Wnt–NAD+ axis is a fundamental regulatory hub in which metabolic state meets developmental signaling and it acts as a metabolic sensor that coordinates tissue regeneration with cellular energy status through compartment specific NAD+ pools.
Wnt signaling regulates NAD+ metabolism by controlling the expression of key biosynthetic enzymes and NAD+ consumers, while NAD+ -dependent proteins modulate Wnt activity through direct interactions and epigenetic modifications.
Sirtuins exhibit tissue-specific and subcellular compartment-dependent roles in Wnt regulation where they function as activators or suppressors depending on the cellular bioenergetic state.
The Wnt–NAD+ axis maintains stem cell function and self-renewal capacity through metabolic/signaling integration, and its disruption during aging leads to declining regenerative capacity.
The progressive dysregulation of compartment-specific Wnt–NAD+ coordination contributes to stem cell exhaustion and multiple pathological conditions, indicating that therapeutic strategies must consider tissue-specific and subcellular targeting.
https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(25)00172-2
