Sphingomyelin is a lipid commonly associated with cholesterol-rich domains . This association arises from the complementary structural and chemical properties of SM and cholesterol. SM has a straight, saturated sphingosine chain that aligns well with the planar geometry of cholesterol, promoting tight packing and enhancing van der Waals interactions. Additionally, the amide group in the sphingosine chain forms hydrogen bonds with the hydroxyl group of cholesterol, further stabilizing cholesterol-SM complexes. This synergy between SM and cholesterol is functionally significant: cholesterol induces an ordering effect on membranes, while SM provides a scaffold that facilitates cholesterol's interaction with other lipids, creating a mutually stabilizing relationship. SM is asymmetrically distributed in the plasma membrane, with a higher concentration in the outer leaflet. This distribution suggests a coordinated role with cholesterol in membrane organization and function. PI(4,5)P 2 plays an important role in endocytosis, exocytosis, cytokinesis, cytoskeleton activation, vesicle fusion, regulation of other phosphorylated PIs, and many signaling pathways . Most PI(4,5)P 2 -dependent processes happen at the cytosolic leaflet. So, it is believed to be localized at the inner leaflet in most of the cells, with a few exceptions, such as Hela and epithelial cells . Few reports exist in the literature focusing on PI(4,5)P 2 transbilayer plasma membrane asymmetry. Only recently, a flippase enzyme was reported for PI(4,5)P 2 , the same as PC flippase .