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The findings of this study suggest that the phosphoinositide phosphatase Sac3 maintains the protein level of scavenger receptor A (SR-A) and regulates foam cell formation. RAW264.7 macrophages were transfected with short hairpin RNAs that target Sac3. The knockdown decreased the level of the cell surface SR-A and suppressed the acetylated low density lipoprotein-induced foam cell formation. The associated regulator of PIKfyve (ArPIKfyve) is a scaffold protein that protects Sac3 from proteasome-dependent degradation. The knockdown of ArPIKfyve decreased Sac3, cell surface SR-A, and foam cell formation. The knockdown of PIKfyve had no effect on SR-A protein levels. These results suggest that the ArPIKfyve-Sac3 complex regulates SR-A protein levels independently of its effect on PIKfyve activity.Sac3 knockdown decreased the foam cell formation in RAW264.7 macrophages.Sac3 knockdown decreased the level of the cell surface SR-A.ArPIKfyve knockdown decreased Sac3, cell surface SR-A, and foam cell formation.The knockdown of PIKfyve had no effect on the cell surface SR-A.ArPIKfyve-Sac3 complex regulates SR-A protein levels independently of PIKfyve.