Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential
Authors:Shima Ebadollahibaruq1,2, Lingbin Meng2 and Feng Hong1,2,*
1 Pelotonia Institute for Immune-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, 410 W 12th Ave, Columbus, OH, 43210, USA. 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, 410 W 12th Ave, Columbus, OH, 43210, USA.
Keywords:
Canopy homolog protein 2, unfolded protein responses, cancer, tumor microenvironment, Endoplasmic reticulum stress, neurodegenerative disease, cardiovascular disease.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no competing interests.
Please cite this article as:
Shima Ebadollahibaruq, Lingbin Meng, Feng Hong (2026). Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential. Cell Stress 10: 19-31. doi: 10.15698/cst2026.03.316
© 2026 Ebadollahibaruq et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Canopy homolog protein 2 (CNPY2), an endoplasmic reticulum (ER) luminal protein exhibits broad tissue distribution and regulates cellular homeostasis, including unfolded protein responses (UPR), mitochondrial dynamics, oxidative stress, and apoptosis. Beyond its role in cancer progression through pathways such as NF-κB, AKT/GSK3β, PI3K/Akt/mTOR and HIF-1α, promoting epithelial-mesenchymal transition (EMT), tumor survival and metastasis, CNPY2 is also critical in non-cancer conditions. In neurodegenerative disorders including Parkinson’s and Huntington’s, it exerts neuroprotective role by reducing oxidative stress and mitochondrial dysfunction. In cardiovascular tissues, CNPY2 leads to hypoxia-driven angiogenesis, tissue repair, and ischemia-reperfusion protection. Moreover, recent meta-analyses have linked CNPY2 downregulation with Keratoconus pathogenesis, further highlighting its tissue- specific roles. Hence, this review meticulously dissects CNPY2’s structural characteristics, expression patterns, and biological functions across cancer, cardiovascular disease, inflammation and neurological disorders, emphasizing its role on tumor initiation, microenvironmental stress, and chemoresistance, and evaluating its potential as a therapeutic target.