MYC alleviates oxalate-induced renal tubular ferroptosis and reshapes the macrophage chemotactic microenvironment by regulating TP53

Injury of renal tubular epithelial cells is a key link in the formation of kidney stones, but its regulatory mechanism, especially the relationship with ferroptosis, remains unclear. In this study, a renal tubular epithelial cell injury model was established in vitro by oxalate (Ox) acting on HK2 cells. In vivo, a calcium oxalate (CaOx) model was established in the kidneys of mice by intraperitoneal injection of 80 mg/kg glyoxalate for 6 days. OE-MYC significantly reduced the adhesion and expansion abilities of cells. The experimental results of Western blot indicated that the upregulation of Solute Carrier Family 7 Member 11 (SLC7A11) and the downregulation of TP53 after OE-MYC effectively inhibited iron death. Compared with the Ox + OE-NC group, the intracellular iron ion concentration and ROS level in the Ox + OE-MYC group were significantly lower. Through in vivo experimental studies, we found that the treatment with OE-MYC effectively alleviated renal damage caused by CaOx. From a mechanistic perspective, MYC can regulate the transcription process of TP53 through direct binding to the promoter. It can also inhibit oxalate-induced ferroptosis of renal tubular epithelial cells by reducing TP53, decrease the binding of HMGB1 to TLR4, and inhibit the NF-κB pathway, thereby promoting the transformation of macrophages to the M2 phenotype and further preventing the formation of stones. In conclusion, MYC alleviates the damage to renal tubular epithelial cells caused by Ox, ferroptosis and the formation of CaOx stones by regulating TP53.