TMEM41B is an endoplasmic reticulum-resident phospholipid scramblase that mediates trans-bilayer shuttling of bulk phospholipids 1. Its primary function involves regulating cellular lipid homeostasis and organelle biogenesis, including lipoprotein secretion, autophagosome formation, and lipid droplet biogenesis 2. TMEM41B functions as a critical host dependency factor for coronavirus and flavivirus replication 34. Post-viral entry, TMEM41B facilitates ER membrane remodeling necessary for forming double-membrane vesicles (DMVs)—the replication organelles essential for viral genome replication 45. During this process, TMEM41B regulates phosphatidylserine distribution to enable DMV closure 5. Additionally, TMEM41B modulates cellular lipid and energy metabolism, particularly mitochondrial beta-oxidation, to support viral replication 6. Loss of hepatic TMEM41B paradoxically triggers nonalcoholic hepatosteatosis due to impaired lipoprotein secretion coupled with activated sterol regulatory element-binding protein signaling 2. Notably, natural polymorphisms in TMEM41B at ~20% frequency in East Asian populations reduce flavivirus susceptibility 3, suggesting therapeutic potential. These findings position TMEM41B as a promising broad-spectrum antiviral target.