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

作者：Yani Pan, Nannan Zhang, Xin Fu, Xinyu Wang, Yuxiang Ma, Qi Chen, Yue Zhou, Hong‐Wen Liu, Yun Zhu, Lei Xu, Qiang Wang, Dongyin Chen, Zhangding Wang, Lei Wang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03564-8 · 被引用次数：5 · 研究领域：Cancer, Lipids, and Metabolism、Metabolism, Diabetes, and Cancer、Peroxisome Proliferator-Activated Receptors

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 aut...