SFTPB encodes surfactant protein B, a critical pulmonary surfactant component that reduces surface tension at the air-liquid interface in alveoli, increasing the collapse pressure of palmitic acid to approximately 70 millinewtons per meter. 1 The protein is produced by alveolar epithelial type 2 cells and functions in maintaining alveolar stability and respiratory gas exchange. 2 Mechanistically, SFTPB participates in surfactant metabolism and processing. Mutations in SFTPB impair normal surfactant processing; however, CRISPR-based correction in patient-derived induced pluripotent stem cells successfully restores this function. 1 Pro-SFTPB, the precursor form, accumulates in progressive pulmonary fibrosis and serves as a biomarker in serum extracellular vesicles, reflecting pro-fibrotic changes originating from alveolar epithelial type 2 cells. 3 Clinically, SFTPB dysfunction is associated with respiratory distress syndrome in premature infants and pulmonary surfactant metabolism dysfunction. Beyond primary surfactant disorders, SFTPB has broader disease relevance: elevated blood SFTPB strongly predicts interstitial lung abnormalities and their progression (OR 3.71), 4 specific SFTPB genetic polymorphisms (rs11130866, rs7316, rs9752) influence COVID-19 severity and treatment requirements, 5 6 and recurrent 3' UTR mutations in SFTPB appear enriched during lung adenocarcinoma evolution in Chinese patients. 7 Additionally, genetically predicted SFTPB levels show inverse association with lung cancer risk. 8