Evidence map›Paper›PMID 42728394›Full record

ArticleNature cancer2026

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

Peixiang Zheng, Yanni Lin, Meiyin Zhang, Zhiyuan Tang, Wenxing Qin, Min Xiao, Xue Sun, Yuli Shen, Zhiqiang Hu, Shuo Ru and 23 more

Abstract read
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Article in Nature cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

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0 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

33 authors.

Peixiang Zheng *Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Yanni Lin *Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Meiyin Zhang *Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Zhiyuan Tang *Department of Pharmacy, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Wenxing Qin *Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.ORCID http://orcid.org/0000-0002-1989-3027
Min XiaoDepartment of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Xue SunDepartment of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Yuli ShenZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Zhiqiang HuZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0003-1313-3470
Shuo RuZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Yuran DuanZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Bofei DongZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Ting WenZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Mengdie LiDepartment of Nutrition and Food Hygiene, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
Hong WuDepartment of Oncology and Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Yueru HouZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Guimei JiZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Zheng WangZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0001-6277-3269
Xiaohong WuNHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, China.ORCID http://orcid.org/0000-0002-8259-3027
Qimin ZhouDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiaoguang LiuCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0001-6977-5128
Gaopeng LiDepartment of Colorectal Surgery and Oncology of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Yuhao WangZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0002-4539-3720
Shengzhong DuanStomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.ORCID http://orcid.org/0000-0002-4866-3167
Yang LuoDepartment of Laboratory Medicine, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, China.ORCID http://orcid.org/0000-0002-0166-9027
Bo ChuDepartment of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.ORCID http://orcid.org/0000-0001-9754-2743
Xu QianDepartment of Clinical Laboratory, Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.ORCID http://orcid.org/0000-0003-0629-4460
Zhimin LuZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0002-2859-2736
Yuan DingDepartment of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. dingyuan@zju.edu.cn.ORCID http://orcid.org/0009-0001-4948-3563
Chuan XuDepartment of Oncology and Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. xuchuan100@163.com.ORCID http://orcid.org/0000-0002-5320-2277
Xu QianDepartment of Nutrition and Food Hygiene, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China. xqianmedres@njmu.edu.cn.ORCID http://orcid.org/0000-0003-1533-8568
Tong LiuDepartment of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China. liutong@hrbmu.edu.cn.ORCID http://orcid.org/0000-0001-9234-1328
Daqian XuZhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xudaqian@zju.edu.cn.ORCID http://orcid.org/0000-0003-0478-2997

Funding

Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2021YFA0805600National Natural Science Foundation of China (National Science Foundation of China) 82072630National Natural Science Foundation of China (National Science Foundation of China) 82402048
6 · The paper itself

Abstract

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.

Identifiers

PMID42728394

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.