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

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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.

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