SDF2L1 (stromal cell-derived factor 2-like 1) is an endoplasmic reticulum (ER)-resident chaperone protein that functions as a critical regulator of protein quality control and metabolic homeostasis. As an ER stress-inducible gene 1, SDF2L1 encodes a protein with an ER-retention motif (HDEL) and belongs to the Pmt/rt protein family 1. Mechanistically, SDF2L1 forms multiprotein complexes with HSP40 co-chaperones like ERdj3 and DNAJB11 to regulate protein folding and prevent aggregation 23. It interacts with the ER-associated degradation (ERAD) machinery and modulates substrate availability for degradation, thereby buffering misfolded protein processing 4. Additionally, SDF2L1 regulates ERAD through interaction with the trafficking protein TMED10 5. Clinically, SDF2L1 dysfunction correlates with metabolic disease: hepatic Sdf2l1 downregulation in obese and diabetic mice impairs glucose homeostasis and promotes fatty liver disease 5, while insufficient induction in diabetic patients associates with insulin resistance and steatohepatitis 5. In cancer, SDF2L1 acts as a tumor suppressor—downexpression occurs in nasopharyngeal carcinoma, and SDF2L1 overexpression inhibits cell proliferation, migration, and invasion 6. Recent evidence suggests SDF2L1 modulates oxLDL-induced ER stress and protein O-mannosylation in cardiovascular and malignant diseases 7. Thus, SDF2L1 represents a potential therapeutic target and biomarker for metabolic and neoplastic diseases.