This study identifies a molecular mechanism of the O-linked N-acetylglucosamine transferase (OGT)-mediated enhancer of zeste homolog 2 (EZH2)/krüppel-like factor 2 (KLF2)/chemokine (C-X-C motif) ligand 1 (CXCL1) axis underlying the hypercalcemia-induced nerve injury in renal failure. Here, CXCL1 is linked to hypercalcemia disease.