UPF1 is an RNA helicase and ATPase that serves as a central regulator of RNA quality control and decay pathways. Its primary function involves nonsense-mediated mRNA decay (NMD), where it recognizes and degrades aberrant mRNAs containing premature termination codons 1. UPF1 undergoes phosphorylation-dependent cycles during NMD, forming surveillance complexes with UPF2 and UPF3 that activate mRNA degradation machinery 1. Beyond classical NMD, UPF1 mediates structure-dependent RNA decay by recognizing highly structured 3'UTRs in collaboration with G3BP1, affecting both coding and noncoding RNAs independently of specific sequences 2. The protein also participates in Staufen-mediated mRNA decay (SMD), where it enhances helicase activity and competes with NMD pathways 3. Disease relevance includes hepatocellular carcinoma, where TRIM34-mediated UPF1 degradation suppresses ferroptosis by preventing GPX4 transcript decay 4. In lung cancer, MET amplification leads to UPF1 phosphorylation, which downregulates STING expression and contributes to immunotherapy resistance 5. UPF1 dysfunction is linked to various human disorders through its critical roles in transcript quality control and cellular homeostasis 6.