Atp9a, a lipid flippase of the class II P4-ATPases, is involved in cellular vesicle trafficking. It plays a role in the recycling pathway from endosomes to the plasma membrane, and is part of an evolutionary conserved complex related to Wntless sorting and Wnt secretion [5,6]. It also has implications in various biological processes and diseases.

In hepatocellular carcinoma, nutrient starvation-induced macropinocytosis is regulated by Atp9a. High levels of Atp9a predict a poor outcome for patients, as it interacts with ATP6V1A, promotes plasma membrane cholesterol accumulation, and drives RAC1-dependent macropinocytosis, which helps the cells tolerate nutrient starvation [1].

In neurodevelopmental disorders, Atp9a deficiency causes autosomal recessive hypotonia, intellectual disability, and attention deficit hyperactivity disorder (ADHD). Atp9a null mice recapitulate the symptoms observed in patients, with abnormal neurite morphology, impaired synaptic transmission, and abnormal endosomal recycling due to its role in modulating small GTPase RAB5 and RAB11 activation [2].

Knockdown of Atp9a in human hepatoma cells leads to a significant increase in extracellular vesicle (EV) release, indicating its role in regulating exosome release, and its overexpression and knockout affect the lipid composition of exosomes [3,4].

In conclusion, Atp9a is crucial for vesicle trafficking-related functions such as endosomal recycling, exosome release, and macropinocytosis regulation. The study of Atp9a-deficient mouse models has revealed its significant roles in hepatocellular carcinoma and neurodevelopmental disorders, providing insights into the underlying mechanisms and potential therapeutic targets for these diseases.