After cisplatin treatment, the Lipin3 deficiency can reduce the ability of Sirt1 in repressing p21, which leads to the overexpression of p21 and further activates the Caspase 3 and GSDME, finally resulting in mitochondrial dysfunction, apoptosis and Caspase 3/GSDME‐dependent secondary pyroptosis in primary tubular epithelial cells (PTECs) and aggravated cisplatin induced AKI. Here, GSDME is linked to acute kidney injury.