CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity

Abstract

Ferroptosis is emerging as a novel mechanism for understanding renal tubular injury in diabetic nephropathy (DN). The mitochondria-associated endoplasmic reticulum membrane (MAM) plays a crucial role in the regulation of numerous cellular processes, including mitochondrial dysfunction and endoplasmic reticulum (ER) stress (ERS). However, the exact mechanism underlying ferroptosis and MAM in DN remains unclear. In this study, we identified that canopy FGF signaling regulator 2 (CNPY2) is upregulated in the renal tubules of DN. Downregulation of CNPY2 alleviated ferroptosis and improved MAM integrity in the renal tubular epithelial cells of db/db mice. Conversely, CNPY2 overexpression aggravated tubular injury in DN by accelerating ferroptosis and disrupting MAM formation. Mechanistically, CNPY2 activated the PERK/ATF4/CHAC1 signaling pathway to facilitate ferroptosis, thus contributing to tubular injury in DN. These findings highlight the critical role of CNPY2 in modulating ferroptosis and MAM formation in DN progression, and suggest that CNPY2 is a feasible therapeutic target for DN.