Zonated cholesterol sensing by SIRT2 drives MASLD-HCC.
Zonated cholesterol sensing by SIRT2 initiates MASLD-related hepatocellular carcinoma, with SIRT2 overexpression in zone 1 causing tumors in mice and humans.
- Why it matters: Understanding how metabolic zonation influences liver cancer development is crucial for targeted therapies, as the regional origin of tumors impacts disease progression and treatment.
- What they did: The study used lineage tracing, genetic manipulation, and human organoids to show that SIRT2 senses cholesterol in zone 1 hepatocytes, triggering reprogramming and tumor formation.
- The result: Inhibiting SIRT2 restores normal cholesterol and bile acid metabolism, enhances immune response, and offers a promising, druggable target for preventing or treating liver cancer.