Zonated cholesterol sensing by SIRT2 drives MASLD-HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), but how metabolic zonation drives regional transformation remains unclear. We identify sirtuin 2 (SIRT2) as a zonated cholesterol sensor that initiates reprogramming to drive MASLD-HCC. Lineage tracing establishes zone 1 hepatocytes as the cellular origin of tumors. SIRT2 overexpression in zone 1 triggers HCC, whereas its deletion prevents carcinogenesis by restoring cholesterol and bile acid metabolism and CD8+ T cell recruitment. Mechanistically, cholesterol binds and activates SIRT2, which deacetylates sterol carrier protein 2 (SCP2) at Lys546, thereby blocking peroxisome proliferator-activated receptor α (PPARα) recruitment to the Cyp7b1 promoter, suppressing alternative bile acid synthesis, and permitting 27-hydroxycholesterol accumulation. SIRT2 inhibition reverses this cascade in mice and human hepatic organoids. Patient specimens confirm zonal SIRT2 and cytochrome P450 7B1 (CYP7B1) dysregulation. Our findings establish spatially compartmentalized cholesterol sensing as a new regulatory layer and identify SIRT2 as a druggable target in liver cancer.