UPF3A is a regulator of nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs containing premature termination codons. UPF3A functions redundantly with its paralog UPF3B to activate NMD, contrary to earlier reports suggesting it acts as an NMD inhibitor 1. The protein associates with the exon junction complex (EJC) and recruits UPF2 to form the UPF1-UPF2-UPF3 surveillance complex that activates NMD. However, UPF3A can activate NMD independently of EJC binding, with its conserved middle domain being critical for activity 2. While single knockout of UPF3A has minimal effects on global NMD activity, co-depletion with UPF3B results in marked NMD inhibition and transcriptome-wide upregulation of NMD substrates 1. Clinically, UPF3A shows disease relevance in colorectal cancer, where high expression correlates with metastasis, poor prognosis, and serves as an independent risk factor for survival 3. Additionally, UPF3A methylation status has potential as a blood-based biomarker for early colorectal cancer detection 4. The gene also shows expression throughout spermatogenesis and may contribute to male infertility 5.