SPRR3 (small proline-rich protein 3) is a cornified envelope precursor protein primarily expressed in oral, esophageal, and bronchial epithelia, where it is strictly linked to keratinocyte terminal differentiation 1. The gene contains characteristic intragenic duplications creating proline-rich repeats and is regulated by multiple differentiation-specific promoter elements including Ets binding sites, AP-1 sites, and ATF/CRE motifs 1. Cigarette smoke upregulates SPRR3 through c-Jun/Fra1 heterodimerization at the AP-1 binding site, indicating involvement in pathogenic keratinization responses 2. Beyond its structural role, SPRR3 has emerged as a regulatory protein in inflammatory diseases. It regulates allergic airway inflammation through the IL-33/ILC2 axis via PI3K/AKT/NF-κB signaling 3, positioning it as a potential asthma therapeutic target. SPRR3 is also implicated in ocular diseases, with shared dysregulation in pterygium and meibomian gland dysfunction involving keratinization pathways 4, and represents a genetic susceptibility factor in atopic dermatitis 5. Clinically, SPRR3 shows prognostic significance in malignancies, with aberrant expression correlating to poorer outcomes across multiple cancer types and potential as a lung adenocarcinoma biomarker 6. Notably, SPRR3 expression is dramatically decreased in esophageal carcinomas compared to normal mucosa 7, suggesting tissue-specific dysregulation in cancer pathogenesis.