NOTUM is a carboxylesterase that serves as a critical negative regulator of Wnt signaling through depalmitoleoylation of WNT proteins, which is essential for their binding to frizzled receptors 1. In aging, NOTUM produced by Paneth cells attenuates intestinal epithelial regeneration by decreasing stemness-maintaining Wnt signaling, with high mTORC1 activity in aged Paneth cells inhibiting PPAR-α activity and increasing NOTUM expression 2. NOTUM plays a dual role in colorectal cancer progression: it initially functions as a tumor suppressor in APC-null adenomas but becomes an oncogene upon progression to adenocarcinoma with P53 loss, with these effects being Wnt-independent and mediated through differential activity on glypicans 3. APC-mutant cells exploit NOTUM secretion to gain clonal advantage over wild-type cells by suppressing their growth and driving differentiation, facilitating early cancer initiation 4. Spatially, NOTUM-expressing epithelial cells are concentrated at the boundary between normal tissue and adenomas, where they activate cancer-related pathways despite lacking morphological changes 5. Therapeutic inhibition of NOTUM shows promise for treating advanced colorectal cancer and promoting regeneration in aged tissues 23.