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STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD

GSE304254 Mus musculus (mouse) RNA-seq (gene expression) 53 samples Submitted 2025/08/21 Platform GPL24247
At a glance

RNA-seq (gene expression) · mouse · 53 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
53 samples: 11 conditions, mostly with about 5 replicates eachGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADDNature · 2025
Summary (written by the submitters)
Conditional deletion of Caspase-8 in epidermal keratinocytes (Casp8E-KO) causes necroptosis-driven lethal dermatitis1-7. Here, we discover that Casp8 loss leads to accumulation of cytosolic DNA responsible for the activation of a cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) gene (STING)-mediated transcriptional program.
Read the full summary ↓
Genetic and biochemical evidence indicate that STING upregulates both Z-DNA binding protein-1 (ZBP1), and mixed lineage kinase domain-like (MLKL). Combined Casp8-deficiency- and STING-activation-driven accumulation of Z-nuclei acids, activates ZBP1 and triggers formation of a ZBP1–RIPK1–RIPK3 complex independently of FADD-RIPK1-RIPK3 complex enabling necroptosis execution. Genetically, we reveal a functional overlap between STING and ZBP1 as drivers of lethal dermatitis independently of TNFR1, uncovering a novel aetiology of necroptotic inflammation. Since gain-of-function mutations in human STING cause STING-Associated Vasculopathy with onset in Infancy (SAVI), we assessed the role of STING-induced necroptosis in SAVI’s aetiology. Chronic activation of STING in patients orchestrates a necroptotic transcriptional program which is confirmed in the N153S-SAVI preclinical mouse model where immune cell–driven pathology and lethality are remarkably rescued by RIPK3 co-deletion. These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both Casp8-deficient inflammation and SAVI and suggest that targeting the ZBP1-RIPK3-MLKL axis holds therapeutic potential for interferonopathies characterised by excessive necroptosis.
Published in
STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD
Kelepouras K, Saggau J, Bonasera D et al. · Nature 2025 · PMID 40834903 · doi:10.1038/s41586-025-09536-4
This dataset
Open GSE304254 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE304254_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1299541 and SRA study SRP605626. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40834903) ↗
Study design
11 conditions, mostly with about 5 replicates each
skin_TPC8 ×5 skin_TPC8STING ×5 skin_TPC8TNFR1 ×5 skin_TPCONTROL ×5 skin_C8TNFR1 ×5 skin_C8 ×5 skin_not_discosed ×5 skin_C8STINGEKO ×5 +3 more

Supports a between-group comparison across 53 samples.

How we read this: 11 replicated groups read from 53 sample titles; they account for 53 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

+ 13 more — browse all 53 samples with per-sample file links →

Datasets on a similar topic

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