Taken together, our results showed that TRIM27 reduced GLIS1 DNA methylation and increased its expression, subsequently activating the Wnt/β‐catenin pathway by inhibiting PRC2 activity through mediating EZH2 ubiquitination degradation, thereby promoting mRTECs dedifferentiation, proliferation, and migration and ultimately alleviating RIRI‐induced AKI (graphical abstract). Here, GLIS1 is linked to acute kidney injury.