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

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains as an aggressive disease, though neoadjuvant chemotherapy (NAC) has approved the clinical outcomes of patients with PDAC. However, the unsatisfactory objective response rate of approximately 20%-30% of NAC warrants investigations into novel combination therapy strategies and our understanding of metabolic determinants to PDAC chemotherapy responsiveness is still limited. Here, we identified Methylmalonate Semialdehyde Dehydrogenase (MMSDH) as a metabolic driver of gemcitabine (GC) poor responsiveness. Mechanistically, MMSDH, a metabolic enzyme involved in valine catabolism, was lactylated at K113 by GCN5 upon hypoxia and interacts with ACSL4 to produce propionyl-CoA for efficient KAT8-mediated ACSL4 K606 propionylation, which enhances ACSL4-HSC70 binding and chaperone-mediated autophagy (CMA)-mediated ACSL4 degradation. Moreover, MMSDH K113la-mediated ACSL4 K606 propionylation is negatively correlated with ACSL4 expression levels and predicts poor chemotherapy outcomes in patients with PDAC. Dietary valine restriction (DVR) combined with gemcitabine synergistically induces ferroptosis in PDAC and suppresses tumor growth. Furthermore, preclinical proof-of-concept studies using MMSDH K113la blocking peptide disrupt GCN5-MMSDH-ACSL4 axis, and elevates gemcitabine-induced ferroptosis to inhibits tumor progression. These findings revealed a previously unknown mechanism by which tumor cells orchestrate valine metabolism and ACSL4 to counteract ferroptosis in the context of oxidative stress and chemotherapy. This discovery shed lights on the potential for developing novel therapeutic strategies targeting the GCN5-MMSDH-ACSL4 axis to improve the responsiveness of PDAC to chemotherapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Daqian Xu  

PROVIDER: PXD065546 | iProX | Fri Jun 27 00:00:00 BST 2025

REPOSITORIES: iProX