Lactylation Converts ABHD6 into a Mitochondrial Regulator that Drives Lenvatinib Resistance in Hepatocellular Carcinoma - PubMed
2 hours ago
- #Mitochondrial Dynamics
- #Lenvatinib Resistance
- #Hepatocellular Carcinoma
- Hepatocellular carcinoma (HCC) often develops resistance to lenvatinib, a frontline tyrosine kinase inhibitor.
- Resistance mechanisms involve metabolic reprogramming and mitochondrial adaptation, with ABHD6 identified as a key driver.
- ABHD6's role in resistance is independent of its catalytic function but requires an unoccupied catalytic site at S148.
- Lactate-driven lactylation of ABHD6 at K245 triggers its mitochondrial translocation, where it acts as a scaffold.
- ABHD6 competitively binds FIS1, displacing DRP1, disrupting mitochondrial fission, and stabilizing hyperfused mitochondria.
- This stabilization suppresses drug-induced apoptosis and ROS generation, conferring lenvatinib resistance.
- Inhibiting lactate production or occupying the S148 site can block ABHD6-FIS1 complex formation, restoring lenvatinib sensitivity.
- Targeting ABHD6's allosteric mechanism is a promising strategy to overcome lenvatinib resistance in HCC.