SEL1L encodes an essential adaptor subunit of the SYVN1 (HRD1) ubiquitin ligase complex that mediates endoplasmic reticulum-associated degradation (ERAD), a critical quality control mechanism for eliminating misfolded ER proteins 1. The SEL1L-HRD1 complex functions as a highly conserved ERAD machinery that maintains ER homeostasis and regulates substrate protein levels in a substrate-specific manner 1. SEL1L enhances SYVN1 stability and promotes the degradation of various misfolded proteins including fibrinogen chains, SERCA2, and leptin receptors through ubiquitin-dependent proteasomal degradation 234. The protein plays crucial roles in hepatic fibrinogen biogenesis, where it degrades misfolded fibrinogen subunits to enable proper complex assembly 2. In POMC-expressing neurons, SEL1L-HRD1 regulates leptin receptor turnover, influencing leptin signaling and diet-induced obesity 4. Human mutations in SEL1L cause severe neurodevelopmental disorders with onset in infancy (ENDI), characterized by hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia 15. These pathogenic variants demonstrate the critical importance of ERAD in human physiology, affecting neurodevelopment, immunity, and survival 5.