Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. ACSS2 is an acetyl-coA synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the non-selective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.