2. Academic Validation
  3. c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation

c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation

  • Cell Death Dis. 2026 Feb 5;17(1):205. doi: 10.1038/s41419-026-08439-0.
Jing Wang 1,  Liyuan Zhang 1,  Keke Chen 2,  Fangze Wei 1,  Wendi Li 1,  Chanjuan Cui 1,  Feng Chen 1,  Bing Wei 3,  Tao Huang 3,  Hezhi Fang 4 5,  Wei Cui 6 7
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • 3 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
  • 4 Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 5 Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 6 Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 7 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. [email protected].
PMID: 41644513 DOI: 10.1038/s41419-026-08439-0
Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells undergo mitochondrial metabolic reprogramming to support their proliferation. However, the mechanisms by which mitochondrial protein quality control (MPQC) regulates cell metabolism remain unclear. Here, we found that c-Myc promotes PDAC cell proliferation by transcriptionally upregulating the expression of GRPEL1, an essential MPQC component. Mechanistically, c-Myc-regulated GRPEL1 maintains Oxidative Phosphorylation (OXPHOS) and minimizes ROS accumulation, thereby facilitating de novo fatty acid (FA) synthesis through the transcriptional upregulation of fatty acid synthase (FASN) expression. Targeting the c-Myc/GRPEL1 axis to block FASN-regulated FA synthesis inhibited PDAC cell proliferation and tumor growth in both cell models and patient-derived organoids (PDOs), whereas FA supplementation partially reversed this inhibitory effect. Clinically, c-Myc expression is positively associated with the levels of MPQC components in pancreatic ductal cells, with GRPEL1 ranking among the top hits. Furthermore, c-Myc, GRPEL1, and FASN are all expressed at higher levels in PDAC tissues than in peri-tumoral pancreatic tissues, and both c-Myc and GRPEL1 expression levels are positively correlated with that of FASN. These findings suggest that therapeutic inhibition of FA synthesis may be promising for treating PDAC patients with active c-Myc/GRPEL1/FASN signaling. Overall, this study demonstrates that FA synthesis mediated by the c-Myc/GRPEL1/FASN axis is essential for PDAC growth.

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