By combining single-cell RNA sequencing analysis, a variety of primary fibroblast and primary intestinal epithelial organoid models, mouse intestinal tissue analysis, transcriptomic studies, and colorectal cancer (CRC) patient cohort survival analyses, we show that NRG1, but not EREG, is sufficient to reprogram the intestinal epithelium into a regenerative, fetal-like state without promoting tumorigenic growth. Here, NRG1 is linked to colorectal cancer.