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  3. Targeting glutaryl-CoA dehydrogenase-driven acetyl coenzyme A acetyltransferase 2 crotonylation dysregulates cholesterol metabolism in pancreatic cancer cells

Targeting glutaryl-CoA dehydrogenase-driven acetyl coenzyme A acetyltransferase 2 crotonylation dysregulates cholesterol metabolism in pancreatic cancer cells

  • Int J Biol Macromol. 2026 Jan;335(Pt 2):149182. doi: 10.1016/j.ijbiomac.2025.149182.
Feng Han 1,  Hao Zhang 2,  Qing Ye 3,  Qu Zhang 4,  Wandi Shen 5,  Ka Bian 1,  Fanghong Chen 6,  Jiayou Guo 7,  Mingchen Mu 8,  Jianxin Ma 9
Affiliations

Affiliations

  • 1 Department of Oncology, Lianyungang Municipal Oriental Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222042, Jiangsu Province, China.
  • 2 Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: zhanghao1702@sjtu.edu.cn.
  • 3 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 4 Department of Radiotherapy Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 The Second Clinical Medical College of Binzhou Medical College, Yantai, 264000, Shandong Province, China.
  • 6 Department of Oncology, Lianyungang Municipal Oriental Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222042, Jiangsu Province, China. Electronic address: cfh880314@163.com.
  • 7 Department of Oncology, Lianyungang Municipal Oriental Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222042, Jiangsu Province, China. Electronic address: 15261379260@163.com.
  • 8 Department of Oncology, Lianyungang Municipal Oriental Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222042, Jiangsu Province, China. Electronic address: 87125571@qq.com.
  • 9 Department of Oncology, Lianyungang Municipal Oriental Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222042, Jiangsu Province, China. Electronic address: 3213766577@qq.com.
PMID: 41285334 DOI: 10.1016/j.ijbiomac.2025.149182
Abstract

Cancer cells rely on the metabolic reprogramming of Amino acids to regulate the production of specific metabolites in the tumor microenvironment and support tumor growth. We demonstrated that the upregulation of glutaryl-CoA dehydrogenase (GCDH), a key gene encoding a metabolic enzyme involved in the conversion of lysine and tryptophan to crotonyl-CoA, was correlated with worse prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), as GCDH depletion inhibits PDAC growth. Mechanistically, GCDH promotes Cholesterol biosynthesis by enhancing the CREB Binding Protein (CBP)-mediated crotonylation (Kcr) modification of acetyl coenzyme A acetyltransferase 2(ACAT2). Importantly, ACAT2-Kcr induces the dissociation of the Insig1-SCAP complex, thereby facilitating the transport and activation of the SCAP-SREBP2 complex during its translocation from the endoplasmic reticulum (ER) to the Golgi apparatus. Conversely, ACAT2 decrotonylation triggers ER stress and promotes the Apoptosis of PDAC cells. This study reveals the roles of GCDH in controlling Cholesterol metabolism and PDAC progression and suggests that GCDH is a new target for therapeutic intervention in patients with PDAC.

Keywords

Acetyl coenzyme A acetyltransferase 2; Cholesterol metabolism; Crotonylation; Glutaryl-CoA dehydrogenase; Pancreatic ductal adenocarcinoma.

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