ORMDL2 is an endoplasmic reticulum membrane protein that plays a critical role in sphingolipid homeostasis by regulating serine palmitoyltransferase (SPT) activity 1. The protein functions as a negative regulator of ceramide biosynthesis: when complexed with SPT, ceramide binding to ORMDL2's N-terminus stabilizes a conformation that blocks SPT substrate entry, preventing excessive ceramide accumulation while maintaining sufficient levels for complex sphingolipid synthesis 1. ORMDL2 is conserved across species from yeast to humans, with functional redundancy among ORMDL family members 2. ORMDL2 has emerged as a multi-functional regulator in cancer biology. In glioblastoma, elevated ORMDL2 expression correlates with poor prognosis and promotes tumor growth through mTORC1-mediated fatty acid metabolism activation 3. ORMDL2 also contributes to immune suppression and therapeutic resistance to DNA damage response inhibitors in glioblastoma 4. Beyond cancer, ORMDL2 variants are associated with increased asthma risk, with asthmatics showing elevated ORMDL2 baseline expression 5. Additionally, rare loss-of-function variants in ORMDL2 are enriched in age-related macular degeneration 6, and upregulated ORMDL2 serves as a diagnostic marker for IgA nephropathy 7. These findings suggest ORMDL2 represents a potential therapeutic target across multiple disease contexts.