MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.

MMSDH-mediated ACSL4 propionylation at K606 is linked to ferroptosis evasion and poor chemotherapy response in PDAC.

• Why it matters: Understanding metabolic mechanisms of chemoresistance in PDAC is crucial to improve treatment outcomes, as current therapies have limited efficacy.
• What they did: The study used molecular and metabolic analyses to show hypoxia-induced MMSDH lactylation interacts with ACSL4, promoting its degradation via propionylation and autophagy, with low ACSL4 levels correlating with poor NAC response.
• The result: Disrupting MMSDH-K113 lactylation enhances ferroptosis and tumor suppression, suggesting the GCN5-MMSDH-ACSL4 axis as a potential target to increase PDAC chemosensitivity.