DERL2 (derlin 2) is an endoplasmic reticulum (ER) membrane protein that functions as a critical component of the ER-associated degradation (ERAD) pathway. Unlike its homolog DERL1, DERL2 is not involved in degradation of MHC class I heavy chains during cytomegalovirus infection. DERL2 operates within the ERAD machinery by facilitating retrotranslocation of misfolded proteins from the ER to the cytosol for proteasomal degradation 1. The protein contains functionally important domains: an N-terminal region (88 amino acids) and a second ER-luminal loop that are required for certain toxin-mediated pathways 2. DERL2 expression is regulated by the minor spliceosome component SCNM1 3, and its transcription is affected in several disease contexts. In hepatocellular carcinoma, elevated DERL2 expression correlates with poor prognosis and promotes tumor growth by stabilizing BAG6, a pro-survival protein 4. DERL2 has been identified as an endoplasmic reticulum stress biomarker in coronary artery disease 5 and shares genetic variants associated with schizophrenia and body mass index comorbidity 6. These findings establish DERL2 as a multifunctional ERAD component with implications in protein quality control, cancer progression, and complex disease pathogenesis.