CNPY2通过调节PERK/ATF4/CHAC1通路和线粒体相关内质网膜（MAM）完整性加重糖尿病肾病中的肾小管细胞铁死亡。
CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity.
作者信息
Chen Jingfang, Liu Dongwei, Lei Lei, Liu Ting, Pan Shaokang, Wang Hui, Liu Yong, Qiao Yingjin, Liu Zhangsuo, Feng Qi
机构信息
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 University, Zhengzhou, 450052, P. R. China.
Department of Cardiology, Henan Provincial Chest Hospital, Chest Hospital of Zhengzhou University, Zhengzhou, 450003, P. R. China.
出版信息
Adv Sci (Weinh). 2025 Jul;12(25):e2416441. doi: 10.1002/advs.202416441. Epub 2025 Apr 11.
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.
铁死亡正成为理解糖尿病肾病（DN）肾小管损伤的一种新机制。线粒体相关内质网膜（MAM）在调节众多细胞过程中起着关键作用，包括线粒体功能障碍和内质网（ER）应激（ERS）。然而，DN中铁死亡和MAM的确切机制仍不清楚。在本研究中，我们发现冠层成纤维细胞生长因子信号调节因子2（CNPY2）在DN的肾小管中上调。下调CNPY2可减轻db/db小鼠肾小管上皮细胞的铁死亡并改善MAM完整性。相反，CNPY2过表达通过加速铁死亡和破坏MAM形成加重DN中的肾小管损伤。机制上，CNPY2激活PERK/ATF4/CHAC1信号通路以促进铁死亡，从而导致DN中的肾小管损伤。这些发现突出了CNPY2在调节DN进展中的铁死亡和MAM形成中的关键作用，并表明CNPY2是DN的一个可行治疗靶点。
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