In this study, we found that cisplatin-induced AKI and renal tubular apoptosis were accompanied by increased phosphorylation of H2AX and p53, expression of p21, and cleavage of caspase 3, while blocking SET8 by either UNC0379 or its specific siRNA inhibited all these responses, suggesting that SET8 mediated DDR contributes to renal epithelial cell death. Here, KMT5A is linked to acute kidney injury.