XRN1 is a major 5'-3' exoribonuclease that catalyzes the processive degradation of decapped mRNAs, the terminal step of the cytoplasmic mRNA decay pathway 1. XRN1 preferentially cleaves 5' monophosphorylated RNA substrates with enhanced kinetics for G4 RNA tetraplexes, and plays specialized roles in nonsense-mediated decay, microRNA-directed decay, and replication-dependent histone mRNA degradation 1. Mechanistically, XRN1 functions within an integrated decay network through direct interactions with the deadenylase CCR4-NOT complex via its C-terminal interacting region (CIR), and with decapping factors including EDC4 and PatL1 2. The EDC4-XRN1 interaction regulates P-body dynamics to coordinate mRNA decapping with 5'-3' decay; disrupting this interaction stabilizes microRNA-targeted mRNAs and enlarges P-bodies 3. Ribosomes serve as platforms linking XRN1 recruitment to mRNA quality control pathways, including nonstop and no-go decay 4. Clinically, XRN1 functions as a tumor suppressor in osteogenic sarcoma and represents a promising therapeutic target in cancer cells dependent on retroelement decay suppression to evade viral mimicry-induced cell death 5. Loss of XRN1 impairs both mRNA levels and translational efficiency of affected transcripts 2.