Collectively, we speculated that TRIM27 reduces GLIS1 DNA methylation and increases its expression, subsequently activating the Wnt/β‐catenin pathway by inhibiting PRC2 activity by mediating the ubiquitination degradation of EZH2, thereby promoting the dedifferentiation, proliferation, and migration of RTECs, and ultimately alleviating the development of RIRI‐induced AKI. Here, GLIS1 is linked to acute kidney injury.