Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription - PubMed
3 hours ago
- #Metabolism
- #Immunotherapy
- #OXCT1
- Increased expression of OXCT1 in hepatocellular carcinoma (HCC) is associated with reduced efficacy of immune checkpoint blockade (ICB) therapy, while its metabolic substrate, β-hydroxybutyrate (BHB), shows a positive correlation.
- Under glucose deprivation, AMPK phosphorylates OXCT1 at S113, triggering its translocation into the nucleus where it interacts with IRF1.
- Nuclear OXCT1 locally depletes BHB, reducing histone H3K9 BHB levels at MHC-I and chemokine gene loci, thereby suppressing their transcription.
- Targeting the AMPK-OXCT1-IRF1 axis, particularly in combination with a ketogenic diet, enhances tumor sensitivity to ICB therapy.
- The study reveals a non-canonical role of nuclear OXCT1 in linking ketone body metabolism to immune gene regulation and immunotherapy response.