AUTHOR=Shen Zhenxuan , Niu Yiting , Chen Hedong , Pan Meikun , Yang Fan , Li Meiying , Zhang Chong , Zhou Yali , Yan Jianguo 
  
TITLE=SEL1L: molecular gatekeeper of the endoplasmic reticulum quality control network
  
JOURNAL=Experimental Biology and Medicine
  
VOLUME=Volume 251 - 2026
  
YEAR=2026
  
URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2026.11350
  
DOI=10.3389/ebm.2026.11350
  
ISSN=1535-3699
  
ABSTRACT=SEL1L (suppressor/enhancer of lin-12-like) is an endoplasmic reticulum (ER) transmembrane protein that serves as a key regulatory molecule in the endoplasmic reticulum-associated degradation (ERAD) pathway, playing a central role in maintaining intracellular protein homeostasis. This paper provides a systematic review of SEL1L’s structural characteristics, the molecular mechanisms by which it forms a functional complex with the E3 ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1, encoded by SYVN1) to synergistically execute ERAD, and its pathophysiological significance in the onset and progression of various diseases. Research indicates that SEL1L dysfunction is closely associated with pathogenic protein aggregation in neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), protein homeostasis imbalances during tumorigenesis, cellular metabolic dysregulation in metabolic disorders (e.g., diabetes, lipid metabolism disorders), and immune system dysfunction. Furthermore, the expression levels or variants of SEL1L exhibit specific alterations across different tumor tissues, suggesting its potential as a disease biomarker and therapeutic target. This paper aims to synthesize existing research, elucidate the ‘gatekeeper’ role of SEL1L in multiple physiological and pathological processes, and explore the prospects for developing novel therapeutic strategies by targeting the SEL1L-HRD1 complex and related pathways.