Update information. Macropinocytosis is an effective strategy against nutrient starvation, which fuels cancer cells grow in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells that frequently exhibit inadequate nutrient supply remains unclear. Here, we reveal that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells, which allowed the cells to acquire extracellular nutrients and support energy supply to maintain rapid proliferation. Furthermore, we determined that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted poor prognosis in hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and subsequently drove RAC1-dependent macropinocytosis. Importantly, macropinocytosis inhibitors significantly suppressed the energy supply and proliferation in hepatocellular carcinoma cells characterized by high ATP9A expression under nutrient-limited conditions. These results revealed a novel route to overcome nutrient starvation in hepatocellular carcinoma cells and identify the key regulator of macropinocytosis in hepatocellular carcinoma.