Abstract
• SMPD3 is identified as a novel host factor that inhibits Hepatitis B virus (HBV) replication at the transcriptional level. • SMPD3 knockdown enhances HBV replication in various cell models, increasing levels of HBsAg, HBeAg, and HBV DNA. • Mechanistic studies reveal SMPD3's inhibition of HBV transcription without affecting RNA stability or promoter activity.