The AMPK-ALDH7A1 axis drives metabolic reprogramming and anti-tumor immunity in hepatocellular carcinoma via KDM5C inhibition.

AMPK/Snf1 phosphorylation of ALDH7A1 promotes its nuclear translocation and local acetate production, inhibiting KDM5C to accumulate H3K4me3 at respiratory genes in HCC models.

• Why it matters: Mitochondrial dysfunction is a hallmark of hepatocellular carcinoma, but the mechanism linking respiratory suppression to metabolic-epigenetic control and anti-tumor immunity is unclear.
• What they did: Using comparative yeast, HCC cell lines, and orthotopic/autochthonous HCC mouse models, the study tests how AMPK/Snf1 phosphorylation regulates ALDH7A1 nuclear localization, acetate generation, and KDM5C/Jhd2 inhibition.
• The result: Loss of AMPK signaling disrupts ALDH7A1 nuclear translocation and enables KDM5C-mediated respiratory suppression, while AMPK-ALDH7A1-acetate-mediated KDM5C inhibition potentiates cGAS-STING signaling, increasing CD8+ T cell infiltration and synergizing with immune checkpoint blockade.

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