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

Limited efficacy of neoadjuvant chemotherapy (NAC) in pancreatic ductal adenocarcinoma (PDAC) underscores the need for novel combination strategies and a deeper understanding of metabolic determinants of chemoresistance. Here we identify methylmalonate semialdehyde dehydrogenase (MMSDH), a valine catabolism enzyme, as a driver of gemcitabine (GC) resistance. Hypoxia induces GCN5-mediated lactylation of MMSDH at K113. Lactylated MMSDH interacts with acyl-CoA synthetase long-chain family member 4 (ACSL4), generating propionyl-CoA to facilitate KAT8-mediated ACSL4 K606 propionylation. This modification enhances ACSL4-HSC70 binding, promoting its degradation through chaperone-mediated autophagy. Critically, this MMSDH-mediated ACSL4 propionylation correlates with low ACSL4 levels and poor NAC response in recipients. Combining dietary valine restriction with GC synergistically induces ferroptosis and suppresses tumor growth. Blocking MMSDH-K113la disrupts this axis, potentiating GC-induced ferroptosis and inhibiting tumor progression. These findings reveal a previously unknown mechanism of ferroptosis evasion through valine metabolism and ACSL4 regulation, nominating the GCN5-MMSDH-ACSL4 axis as a therapeutic target to enhance PDAC chemosensitivity.