biostudies-literatureJiang XNCI NIH HHSNIGMS NIH HHS116384https://www.ebi.ac.uk/biostudies/studies/S-EPMC12908447biostudies-literatureUnknown44(10)Spliceosome inhibitors emerged as promising anticancer agents. Recent studies have demonstrated that spliceosome-targeted therapies (STTs) trigger antitumor immune responses by inducing the accumulation of right-handed double-stranded (ds)RNA (A-RNA), resulting in the activation of RIG-I-like receptors (RLRs) and type I interferon-driven antiviral responses. Here, we show that spliceosome inhibition by pharmacological or genetic neutralization of SF3B1 activity induces the accumulation of endogenous left-handed dsRNAs (Z-RNAs) derived from intron-retained RNAs. These Z-RNAs activate the Z-form nucleic acid-sensor ZBP1, which triggers cell death in mouse embryonic fibroblasts and small cell lung cancer (SCLC) cells. Spliceosome inhibition induced potent ZBP1-dependent cell death in cancer-aCell reportsSpliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer.PMC12908447R37 CA283552T32 GM142606U54 CA221704Liu XZhang TCanadas IKim WJiang XMa XZhou YBalachandran SfalseSpliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer.Spliceosome inhibitors emerged as promising anticancer agents. Recent studies have demonstrated that spliceosome-targeted therapies (STTs) trigger antitumor immune responses by inducing the accumulation of right-handed double-stranded (ds)RNA (A-RNA), resulting in the activation of RIG-I-like receptors (RLRs) and type I interferon-driven antiviral responses. Here, we show that spliceosome inhibition by pharmacological or genetic neutralization of SF3B1 activity induces the accumulation of endogenous left-handed dsRNAs (Z-RNAs) derived from intron-retained RNAs. These Z-RNAs activate the Z-form nucleic acid-sensor ZBP1, which triggers cell death in mouse embryonic fibroblasts and small cell lung cancer (SCLC) cells. Spliceosome inhibition induced potent ZBP1-dependent cell death in cancer-a2025-01-01T00:00:00Z2025 Oct2026-07-16T05:09:03.392Z2026-07-10T03:09:08.212ZS-EPMC129084474104651410.1016/j.celrep.2025.116384