Hao Wang,1,* Zhongquan Yi,2,* Song Yan,3,* Yihao Wang,1 Weisong Zhang,1 Rongqi Guo,1 Yangyang Li,1 Rui Wang,1 Heng Li,2 Xia Li,4 JianXiang Song1 

1Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, 224000, People’s Republic of China; 2Department of Central Laboratory, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, 224000, People’s Republic of China; 3Department of Thoracic Surgery, Sheyang County People’s Hospital, Yancheng, Jiangsu, People’s Republic of China; 4Department of General Medicine, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, 224000, People’s Republic of China

*These authors contributed equally to this work

Correspondence: JianXiang Song, Department of Cardiothoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, No. 2, West Xindu Road, Yancheng, Jiangsu Province, 224000, People’s Republic of China, Email jxsongycsy@163.com Xia Li, Department of General Medicine, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, 224000, People’s Republic of China, Email ycsy161317@163.com

Abstract: ORMDL proteins (ORMDL1, ORMDL2, ORMDL3) are transmembrane proteins in the endoplasmic reticulum (ER) that regulate sphingolipid metabolism, maintain ER homeostasis, and modulate cellular stress responses. They influence cell proliferation, apoptosis, and metabolic balance. Recent studies have highlighted the altered expression and function of ORMDL proteins in various tumors, including breast cancer, DLBCL, colorectal cancer, and lung cancer. ORMDLs negatively regulate serine palmitoyltransferase (SPT), affecting ceramide and sphingolipid metabolism, which plays a key role in tumor cell proliferation, invasiveness, and resistance to therapy. The dysregulation of ORMDL expression may disrupt sphingolipid metabolism, trigger ER stress, and impair autophagy. Investigating ORMDL functions in cancer could lead to novel insights into tumor development and progression. ORMDL expression may serve as a potential biomarker for cancer diagnosis, prognosis, and therapeutic response prediction. Targeting ORMDL or its metabolic networks offers promising strategies for cancer therapy. Although research on ORMDLs is still in its early stages, further studies are needed to explore their roles in the tumor microenvironment, interactions with the immune system, and applications in personalized medicine. A deeper understanding of ORMDL proteins will enhance tumor diagnosis, treatment, and the development of new therapeutic approaches.

Keywords: malignant tumors, ORMDL, molecular targeted therapy, sphingolipid metabolism