Paliperidone Inhibits Ferroptosis Mediated by Autophagy in Renal Tubular Epithelial Cells by Targeting CHAC1

Abstract

Renal tubular epithelial cell injury is a significant factor in the formation of kidney stones. However, the regulatory mechanisms behind this injury, especially the association with autophagy-mediated ferroptosis, remain unclear. This study first identified the upregulated ferroptosis related gene ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1) in kidney stone samples through bioinformatics analysis. Subsequently, a damage model is established by treating renal tubular epithelial cells (HK-2) cells with calcium oxalate (CaOx) and investigated its function by downregulating CHAC1 expression through shRNA transfection. Autophagy status and oxidative stress are evaluated by detecting autophagy (LC3I, LC3II, Beclin 1) and ferroptosis (GPX4) related protein expression using GFP-LC3 adenovirus and Western Blot. In addition, the interaction between small molecule drug Paliperidone (Pali) and CHAC1 is also investigated through molecular docking and cell thermal migration assays to explore therapeutic potential. CHAC1 is upregulated in kidney stones and associated with ferroptosis. Knockdown of CHAC1 weakened CaOx-induced autophagy and ferroptosis. Moreover, Pali can target CHAC1 protein, reduce CHAC1 activity, and inhibit autophagy-mediated ferroptosis during cellular injury. Pali can inhibit autophagy-mediated ferroptosis in renal tubular epithelial cells by targeting CHAC1, offering a new direction for the treatment of kidney stones.