Lipin3 deficiency aggravates cisplatin induced acute kidney injury via activating Sirt1-p21-Caspase 3-GSDME pyroptosis pathway

Lipin proteins, including Lipin 1, Lipin 2 and Lipin3, play a vital role in lipid metabolism. Despite their significance, there is limited understanding of the involvement of Lipin proteins in kidney diseases. This study aims to elucidate the specific functions of Lipin 3 in the context of acute kidney injury (AKI). In the present study, Lipin3 levels were analyzed in AKI public database, kidney tissues from AKI patients and cisplatin induced mice models, as well as cisplatin induced HK2 cells. A <i>Lipin3</i> knockout (<i>Lipin3</i>-KO) mouse model was generated to investigate the pathophysiological roles of Lipin3 in the kidneys. The underlying mechanisms were further examined in primary tubular epithelial cells (PTECs) and HK2 cells <i>in vitro</i>. The findings indicated that (1) Lipin3 was obviously increased in AKI patients, as well as cisplatin induced mice and cells; (2) Lipin3-null mice presented with more severe AKI symptoms compared to WT mice after cisplatin treatment; (3) Lipin3 played crucial role in regulating cell death and mitochondrial function after cisplatin treatment; (4) In terms of mechanism, Lipin3 regulated these phenotypes through its interaction with Sirt1, which activated the p21-Caspase 3-GSDME pathway. Our study suggests that Lipin3 could be pivotal in pyroptosis and AKI. Decreased Lipin3 levels in the kidney may potentially contribute as a risk factor for exacerbating AKI.