2. Academic Validation
  3. Pharmacological induction of acetyl-CoA carboxylase 1 autophagic degradation attenuates lipid accumulation and cholangiocarcinoma progression

Pharmacological induction of acetyl-CoA carboxylase 1 autophagic degradation attenuates lipid accumulation and cholangiocarcinoma progression

  • J Exp Clin Cancer Res. 2025 Nov 25;44(1):310. doi: 10.1186/s13046-025-03564-8.
Yani Pan # 1,  Nannan Zhang # 2,  Xueni Fu # 1,  Xinyu Wang # 3,  Yichun Ma 4,  Qi Chen 3,  Yue Zhou 5,  Hongwen Liu 5,  Yun Zhu 6,  Lei Xu 5,  Qiang Wang 7,  Dongyin Chen 8,  Zhangding Wang 9,  Lei Wang 10 11
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China.
  • 2 Department of Pharmacy, Shidong Hospital, Yangpu District, Shanghai, 200438, China.
  • 3 Department of Gastroenterology, Nanjing Drum Tower Hospital, Drum Tower Clinical Medical College of China Pharmaceutical University, Nanjing, 210000, China.
  • 4 Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China.
  • 5 Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, 210000, People's Republic of China.
  • 6 Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China.
  • 7 Department of Hepatobiliary Surgery, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People's Republic of China.
  • 8 International Joint Laboratory for Drug Target of Critical Illnesses, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu Province, 210000, People's Republic of China. [email protected].
  • 9 Department of Hepatobiliary Surgery, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People's Republic of China. [email protected].
  • 10 Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210000, China. [email protected].
  • 11 Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, 210000, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41291880 DOI: 10.1186/s13046-025-03564-8
Abstract

Background: Aberrant glycogen metabolism drives lipid accumulation and adaptive lipid homeostasis reprogramming, a metabolic adaptation critical for sustaining malignant progression and chemoresistance in cholangiocarcinoma (CCA). While our prior study highlighted glycogen degradation as pivotal for CCA tumorigenesis, the molecular mechanisms governing lipogenesis and its therapeutic exploitation remain elusive.

Methods: We performed single-cell RNA Sequencing to explore metabolic status in CCA. A high-throughput screening of 994 bioactive compound library was performed to identify pharmacological agents capable of inhibiting CCA and targeting this metabolic vulnerability. The drug efficacy was demonstrated through in vitro and in vivo experiments. Additionally, a biotinylated WA derivative was synthesized and its target was investigated using liquid chromatography-tandem mass spectrometry. Validating the clinical potential of the compound for targeted antitumor therapy in combination with gemcitabine in vivo.

Result: Through integrated multi-omics analysis, we identified pronounced lipid droplet accumulation in CCA tissues. Subsequent high-throughput screening of bioactive compounds revealed Withaferin A (WA) as a potent dual suppressor of lipid deposition and cholangiocarcinogenesis. Mechanistically, WA directly binds Acetyl-CoA Carboxylase 1 (ACC1), inhibiting its catalytic conversion of acetyl-CoA to malonyl-CoA. Notably, resultant malonyl-CoA depletion abolished ACC1 auto-malonylation, thereby enhancing SQSTM1/p62-mediated cargo recognition and triggering selective autophagic degradation, consequently disrupting de novo lipogenesis and lipid droplet accumulation. Therapeutically, WA synergized with gemcitabine to enhance antitumor efficacy and prolong survival in preclinical models.

Conclusion: Our study confirms that pharmacological blockade of ACC1 significantly inhibits de novo lipogenesis and CCA tumorigenesis, suggesting that WA may serve as a potential small-molecule inhibitor targeting lipid metabolism for CCA treatment.

Keywords

Acetyl coenzyme A carboxylase 1; Cholangiocarcinoma; Lipid metabolism; Withaferin A.

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