Related Experiment Video

Updated: Jan 16, 2026

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
07:23

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

Published on: May 30, 2025

1.1K

Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer

Xinpei Jiang1, Xueying Ma2, Yunyun Zhou3

  • 1Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Cancer Epigenetics Institute, Fox Change Cancer Center, Philadelphia, PA, USA; Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA; Biomedical Science Graduate Program, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Cell Reports
|October 5, 2025
PubMed

Insights

Spliceosome inhibitors trigger Z-form RNA (Z-RNA) accumulation, activating ZBP1-dependent cell death. This mechanism enhances immunotherapy response in small cell lung cancer models.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Spliceosome inhibitors are investigated as anticancer agents.
  • Current spliceosome-targeted therapies (STTs) activate antiviral responses via right-handed dsRNA (A-RNA) and RIG-I-like receptors (RLRs).
  • A gap exists in understanding alternative mechanisms of spliceosome inhibitor-induced immune activation.

Purpose of the Study:

  • To investigate the alternative mechanisms by which spliceosome inhibitors modulate the tumor microenvironment (TME).
  • To explore the role of left-handed dsRNA (Z-RNA) and ZBP1 in spliceosome inhibitor-mediated anticancer effects.
  • To evaluate the potential of ZBP1-dependent cell death as a strategy to enhance immunotherapy in resistant cancers.

Main Methods:

  • Pharmacological and genetic inhibition of SF3B1 activity.
  • Analysis of Z-RNA accumulation in response to spliceosome inhibition.
  • Assessment of ZBP1 activation and ZBP1-dependent cell death in mouse embryonic fibroblasts and small cell lung cancer (SCLC) cells.
  • Evaluation of immunotherapy response in SCLC mouse models with spliceosome inhibition.

Main Results:

  • Spliceosome inhibition induces endogenous Z-RNA accumulation from intron-retained RNAs.
  • Z-RNA activates ZBP1, triggering cell death in fibroblasts and SCLC cells.
  • ZBP1-dependent cell death in cancer-associated fibroblasts enhances immunotherapy efficacy in SCLC models.

Conclusions:

  • Spliceosome inhibitors can generate Z-RNA, inducing ZBP1-dependent cell death in the TME.
  • This approach offers a novel therapeutic strategy to overcome resistance and enhance immunotherapy in cancers.
  • Targeting ZBP1 activation via spliceosome inhibition presents a promising avenue for cancer treatment.
Keywords:
CP: CancerCP: Molecular biologySCLCSF3B1STTsZ-RNAZBP1immunotherapynecroptosissmall cell lung cancerspliceosomespliceosome-targeted therapy

More Related Videos

A Reporter Based Cellular Assay for Monitoring Splicing Efficiency08:53

A Reporter Based Cellular Assay for Monitoring Splicing Efficiency

Published on: September 15, 2021

3.2K
Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

11.4K

Related Concept Videos

RNA Splicing01:32

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
60.3K
siRNA - Small Interfering RNAs02:30

siRNA - Small Interfering RNAs

Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
18.4K
Experimental RNAi02:15

Experimental RNAi

RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
7.3K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
8.3K
RNA Interference01:23

RNA Interference

RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
27.8K
MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
3.8K