Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.

Nuclear OXCT1 reduces MHC-I gene transcription by suppressing histone β-hydroxybutyrylation in hepatocellular carcinoma cells.

• Why it matters: Understanding how metabolic factors influence immunotherapy responses is crucial, as current knowledge remains limited. Identifying mechanisms that modulate immune gene expression could improve treatment strategies.
• What they did: The study used multiomics analysis of HCC tumor biopsies and found that increased OXCT1 expression correlates with decreased ICB efficacy, while its substrate BHB has the opposite effect; mechanistically, glucose deprivation promotes nuclear translocation of OXCT1, which interacts with IRF1 to suppress histone H3K9 BHB at immune gene loci.
• The result: Targeting the AMPK-OXCT1-IRF1 pathway enhances tumor sensitivity to ICB, suggesting that nuclear OXCT1's regulation of ketone body metabolism and immune gene transcription influences immunotherapy outcomes.