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Publications

Journal Article Ppublish

PubMed: 42728345 DOI: 10.1038/s41388-026-03979-3

Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.

Oncogene 45(43):4597-4612

Authors: Weidong Yu, Bo Wang, Fanhao Meng, Xiaojun Ren, Danyi Zhou, Huanxin Wei, Zhengquan Yang, Hongwei Sun, Minghua Jiang, Tao Xia, Wei Cui, Hezhi Fang

Affiliations

  • Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
  • Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
  • 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, 100000, China.
  • Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. 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, 100000, China.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells rely on fatty acid oxidation (FAO) for proliferation; however, the regulatory mechanisms governing this dependency and their clinical implications remain unclear. Here, we report that PDAC patients exhibit decreased plasma levels of propionyl-CoA intermediates, alongside accelerated propionyl-CoA catabolic activity within both human PDAC tumors and Pdx1-Cre/Kras G12D/+/Trp53 R172H/+ (KPC) mouse tumors. Specifically, PDAC cells upregulate propionyl-CoA carboxylase (PCC) to accelerate propionyl-CoA catabolism, thereby establishing a metabolic signature distinct from that of healthy tissues. Mechanistically, PCC is essential for PDAC growth, not by fueling the TCA cycle, but by preventing toxic propionyl-CoA accumulation. We further demonstrate that elevated propionyl-CoA leads to the propionylation-induced inactivation of the mitochondrial fatty acid oxidation (FAO) enzyme ACAA2 at Lysine 137, thereby blocking the FAO flux required for tumor proliferation. Moreover, high PCCA expression in patient PDAC tumors is significantly associated with decreased lipid accumulation, and PDAC cells with high PCC levels are more sensitive to etomoxir-induced cell proliferation arrest. These findings establish the PCC-ACAA2 axis as a critical metabolic vulnerability and a promising target for diagnostic and therapeutic interventions in PDAC.

MeSH

Cells, Pancreatic Neoplasms, Coenzyme A, Neoplasms, Fatty Acids