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PXD065546
PXD065546 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy |
| Description | 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. |
| HostingRepository | iProX |
| AnnounceDate | 2025-06-27 |
| AnnouncementXML | Submission_2026-06-03_17:55:39.814.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Peixiang Zheng |
| SpeciesList | scientific name: Homo sapiens; NCBI TaxID: 9606; |
| ModificationList | No PTMs are included in the dataset |
| Instrument | 4800 Plus MALDI TOF/TOF |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2025-06-27 00:32:31 | ID requested | |
| ⏵ 1 | 2026-06-03 17:55:40 | announced |
Publication List
| Dataset with its publication pending |
Keyword List
| submitter keyword: ACSL4,MMSDH, ferroptosis, hypoxia |
Contact List
| Daqian Xu | |
|---|---|
| contact affiliation | Zhejiang University |
| contact email | xudaqian@zju.edu.cn |
| lab head | |
| Peixiang Zheng | |
| contact affiliation | Zhejiang University |
| contact email | peixiangzheng7@gmail.com |
| dataset submitter | |
Full Dataset Link List
| iProX dataset URI |
