ZFP36L2: terminating the stress response and regenerating the intestine

ZFP36L2 helps the mouse intestine recover, while enabling colorectal cancer cells in models to establish themselves in a new organ

In a Nature paper published on August 5, 2026, researchers described ZFP36L2, a protein that terminates the stress program in intestinal cells after injury. In experiments with mice, the intestinal epithelium recovered less effectively without this protein. In colorectal cancer models, suppressing ZFP36L2 prevented tumor cells from colonizing other organs.

The intestinal lining renews itself almost continuously. Stem cells reside at the base of its crypts, which are small depressions in the mucosa, and give rise to new epithelial cells. Injury can deplete this stem cell pool. When that happens, some mature cells revert to an earlier state and replenish the pool.

The authors of the Nature paper traced what happens between injury and this return to an earlier state. First, the cell activates a stress program. ZFP36L2 then binds stress-response mRNAs, the working copies of genetic instructions, and helps degrade them. Once these signals subside, the cell can reacquire the properties of an intestinal stem cell and contribute to tissue repair.

“Cells cannot return to a stem cell state while the alarm is still sounding,” senior author Karuna Ganesh said when describing this transition in a piece republished by OncoDaily.

The authors tested this sequence in cells, organoids, which are small laboratory-grown tissue models, and mice. They disabled Zfp36l2, the gene encoding this protein, in the intestinal epithelium of mice. After experimentally induced colitis and after targeted depletion of these stem cells, the stem cell pool in the crypts recovered less effectively. In experiments with mice transplanted with organoids derived from patient tumors, suppressing ZFP36L2 prevented tumor cells from establishing themselves in the liver and lungs.

In colorectal cancer models, a cell that reaches another organ must also survive stress and regain stem cell properties. This allows it to establish itself there and begin growing. In these models, the same transition between cellular states contributes both to intestinal healing and to metastasis. Any attempt to use this transition for tissue repair would therefore need to target the appropriate tissue at the appropriate time.