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

MMSDH-driven ACSL4 propionylation promotes ferroptosis evasion, reducing chemotherapy effectiveness in hypoxic pancreatic cancer by 50%.

• Why it matters: Understanding metabolic mechanisms of chemoresistance in PDAC is critical to improve treatment outcomes, as current therapies often fail due to tumor adaptation.
• What they did: The study used molecular and metabolic analyses to identify MMSDH's role in promoting ACSL4 propionylation via hypoxia-induced lactylation, linking it to ferroptosis suppression.
• The result: Disrupting the MMSDH-ACSL4 pathway enhances ferroptosis and tumor sensitivity to gemcitabine, suggesting new strategies combining dietary valine restriction and targeted therapy to overcome resistance.