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

Jingfang Chen; Dongwei Liu; Lei Lei; Ting Liu; Shaokang Pan; Hui Wang; Yong Liu; Yingjin Qiao; Zhangsuo Liu; Qi Feng

doi:10.1002/advs.202416441

journal article·2025-07Open access

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

Jingfang Chen, Dongwei Liu, Lei Lei, Ting Liu, Shaokang Pan, Hui Wang, Yong Liu, Yingjin Qiao, Zhangsuo Liu, Qi Feng

Advanced Science· Volume 12· Issue 25

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Abstract

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.

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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Cancer-related molecular mechanisms research · Epigenetics and DNA Methylation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Nephrology, the First Affiliated Hospital of Zhengzhou University Research Institute of Nephrology, Zhengzhou University Traditional Chinese Medicine Integrated Department of Nephrology，the First Affiliated Hospital of Zhengzhou University Henan Province Research Center for Kidney Disease，the First Affiliated Hospital of Zhengzhou University Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province the First Affiliated Hospital of Zhengzhou...

Department of Cardiology Henan Provincial Chest Hospital Chest Hospital of Zhengzhou University Zhengzhou 450003 P. R. China

Tianjian Laboratory of Advanced Biomedical Sciences Academy of Medical Sciences Zhengzhou University Zhengzhou 450001 P. R. China

Innovation Center of Basic Research for Metabolic‐Associated Fatty Liver Disease Ministry of Education of China, P. R. China

Department of Cardiology the First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 P. R. China

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