BPIFB3 (BPI fold containing family B member 3) is an endoplasmic reticulum (ER)-localized protein that functions as a negative regulator of enterovirus replication while serving as a positive regulator of flavivirus infection, highlighting its dual role in viral-host interactions. 1 2 Mechanistically, BPIFB3 controls autophagy through a noncanonical pathway independent of core autophagy initiation machinery. 1 During enterovirus infection, BPIFB3 silencing enhances basal autophagy and increases coxsackievirus B (CVB) replication, whereas BPIFB3 overexpression suppresses both autophagy and viral replication. 1 Conversely, in flavivirus infections, BPIFB3 positively regulates dengue virus (DENV) and Zika virus (ZIKV) replication by regulating ER morphology and preventing RETREG1-dependent reticulophagy-mediated ER degradation. 2 Beyond viral biology, BPIFB3 functions as a serous glandular cell-derived antimicrobial protein involved in innate immune defense. Expression of BPIFB3 is remarkably reduced in nasal polyps regardless of age, suggesting its importance in mucosal immunity. 3 The gene is also involved in egg cuticle deposition in avian species and responds to Salmonella infection in poultry. 4 5 BPIFB3 represents a novel therapeutic target for modulating viral infections through selective manipulation of autophagic pathways.