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Zonated Cholesterol Sensing by SIRT2 Drives MASLD-HCC

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC). 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE343566 | GEO | 2026/09/17

REPOSITORIES: GEO

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Zonated Cholesterol Sensing by SIRT2 Drives MASLD-HCC [Spatial transcriptomics]

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