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Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC

GSE296668 Mus musculus (mouse) RNA-seq (gene expression) 21 samples Submitted 2025/09/17 Platform GPL18480
At a glance

RNA-seq (gene expression) · mouse · 21 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
21 samples: 7 × Liver tumor, 4 weeks post AAV8-TTR-Cre injection, mouse vs 5 × Liver tumor, 4 weeks post AAV8-YFP injection, mouse vs 5 × Liver tumor, 8 weeks post AAV8-TTR-Cre injection, mouse vs 4 × Liver tumor, 8 weeks post AAV8-YFP injection, mouseGroups 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
ACLY inhibition promotes tumour immunity and suppresses liver cancerNature · 2025
Summary (written by the submitters)
Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC). While immune cell metabolism influences effector function, the impact of tumor metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY), a key enzyme linking catabolic and anabolic processes, supports lipid metabolism and gene regulation.
Read the full summary ↓
Although ACLY inhibition shows anti-proliferative effects in various tumors, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. Using a mouse model of MASH-driven HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumors reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 with cryo-EM structural analysis revealing EVT0185-CoA directly interacts with ACLY’s CoA binding site. Oral delivery of EVT0185 in four mouse models of MASH-HCC dramatically reduces tumor burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumor ACLY with increases in CXCL13, tumor infiltrating B-cells and tertiary lymphoid structures. Remarkably, the depletion of B cells blocked the anti-tumor effects of ACLY depletion. Together, these findings illustrate how targeting tumor metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
Published in
ACLY inhibition promotes tumour immunity and suppresses liver cancer
Gautam J, Wu J, Lally JSV et al. · Nature 2025 · PMID 40739358 · doi:10.1038/s41586-025-09297-0
This dataset
Open GSE296668 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 GSE296668_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 PRJNA1260482 and SRA study SRP583910. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40739358) ↗
Study design
7 × Liver tumor, 4 weeks post AAV8-TTR-Cre injection, mouse vs 5 × Liver tumor, 4 weeks post AAV8-YFP injection, mouse vs 5 × Liver tumor, 8 weeks post AAV8-TTR-Cre injection, mouse vs 4 × Liver tumor, 8 weeks post AAV8-YFP injection, mouse

Supports a between-group comparison across 21 samples.

How we read this: 4 replicated groups read from 21 sample titles; they account for 21 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
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