Imaging · study · 2026
Zonated Cholesterol Sensing by SIRT2 Drives MASLD-HCC [Spatial transcriptomics]
Listed in NCBI GEO
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC).
Description
How liver metabolic zonation dictates regional malignant transformation remains unclear. We identify SIRT2 as a zonated cholesterol sensor that initiates periportal metabolic reprogramming to drive MASLD-HCC.
Lineage tracing establishes zone 1 hepatocytes as the exclusive tumor origin. Spatially targeted manipulation demonstrates that SIRT2 overexpression in zone 1 is sufficient to trigger HCC, while its deletion restores cholesterol homeostasis, reactivates bile acid metabolism, recruits tumoricidal CD8+ T cells, and completely prevents carcinogenesis. Mechanistically, cholesterol binding directly activates SIRT2, which deacetylates SCP2 at K546, impairs its nuclear translocation and coactivation of PPARα at the Cyp7b1 promoter, thereby suppressing alternative bile acid synthesis and permitting oncogenic 27-OHC accumulation.
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Pharmacological SIRT2 inhibition reverses this pathogenic cascade in mice and human hepatic organoids. The progressive zonal dysregulation of SIRT2 and CYP7B1 during MASLD-HCC progression is confirmed in patient specimens. Our findings establish spatially compartmentalized cholesterol sensing as a new layer of metabolic regulation and identify SIRT2 as a druggable metabolic target for metabolic liver cancer.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343862 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343862 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1513047 ncbi.nlm.nih.gov/bioproject/PRJNA1513047 ↗
project · from NCBI GEO
Topics
- Stated by source
- Mus musculus · Other
- From keywords
- Life Sciences
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE343862 | 7 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:other | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |