biostudies-literatureUnknown8(1)Lockbaum GJXRN1 (5'-3' exoribonuclease 1) degrades RNA from the 5' → 3' direction and utilizes both single- and double-stranded RNA as substrates. XRN1 plays a critical role in mRNA turnover as well as regulating the cellular response to viral infection. XRN1 also protects the cell by preventing endogenous double-stranded RNA accumulation. XRN1 was identified as a putative vulnerability in a subset of cancer cell lines through analysis of publicly available CRISPR data. The role of XRN1 was explored using a set of non-small cell lung cancer cell lines with differential predicted XRN1 dependency to validate XRN1 as an oncology target. In predicted sensitive cell lines, XRN1 knockout reduced proliferation, increased apoptosis and activated the pPKR and MDA5 dsRNA sensing pathways. To facilitate drug diCommunications biology589https://www.ebi.ac.uk/biostudies/studies/S-EPMC11982291biostudies-literatureCharacterization of exoribonuclease XRN1 as a cancer target and identification of adenosine-3',5'-bisphosphate as a potent enzyme inhibitor.PMC11982291Wu JSilver SJLiu JBlakemore SJSickmier EADuncan KWShehaj LYao SRibich SShen SACase ALynes MMBuker SMHolt NBoriack-Sjodin PANayak SPLockbaum GJGrigoriu SSparling BAKnockenhauer KERaman ACopeland RAfalseCharacterization of exoribonuclease XRN1 as a cancer target and identification of adenosine-3',5'-bisphosphate as a potent enzyme inhibitor.XRN1 (5'-3' exoribonuclease 1) degrades RNA from the 5' → 3' direction and utilizes both single- and double-stranded RNA as substrates. XRN1 plays a critical role in mRNA turnover as well as regulating the cellular response to viral infection. XRN1 also protects the cell by preventing endogenous double-stranded RNA accumulation. XRN1 was identified as a putative vulnerability in a subset of cancer cell lines through analysis of publicly available CRISPR data. The role of XRN1 was explored using a set of non-small cell lung cancer cell lines with differential predicted XRN1 dependency to validate XRN1 as an oncology target. In predicted sensitive cell lines, XRN1 knockout reduced proliferation, increased apoptosis and activated the pPKR and MDA5 dsRNA sensing pathways. To facilitate drug di2025-01-01T00:00:00Z2025 Apr2026-06-01T17:57:01.505Z2025-07-14T03:02:39.114ZS-EPMC119822914020503110.1038/s42003-025-08005-y