IFNL3 (interferon lambda 3) is a type III interferon cytokine that plays a critical role in antiviral host defense, predominantly in epithelial tissues 1. It functions by binding to a heterodimeric receptor composed of IL10RB and IFNLR1, activating JAK/STAT signaling to induce interferon-stimulated genes that establish an antiviral state [UniProt]. IFNL3 demonstrates potent antiviral activity against multiple viruses, including hepatitis C virus (HCV), through induction in primary hepatocytes with >1,000-fold expression upon viral stimulation 2. Unlike type I interferons, IFNL3 has restricted receptor distribution, limiting its activity primarily to epithelial cells due to epithelial-specific IFNLR1 expression [UniProt]. IFNL3 genetic polymorphisms (particularly rs12979860 and rs8099917) strongly predict spontaneous HCV clearance and treatment response 34, with favorable genotypes associated with enhanced IFNL3 induction in hepatocytes 2. These variants also influence hepatitis B treatment outcomes and correlate with hepatic inflammation and fibrosis severity across viral and nonviral liver diseases 56. Clinically, IFNL3 genotyping shows potential as a predictive biomarker for antiviral therapy outcomes and HCC risk stratification, though its role in other viral infections like HPV remains unclear 7.