Figure 3.

Metabolic therapy targeting cholesterol trafficking in GBM. Cholesterol transport disorder is closely associated with autophagy and apoptosis. Archazolid B inhibits NPC1, which hinders the release of cholesterol from lysosomes, resulting in inhibition of cell viability. Loperamide and pimozide impair lysosomals' function and induce accumulation of ceramides in lysosomal by inhibiting SMPD1. Ceramides and their hexosylmetabolites contribute to the disruption of lysosomal degradation. The accumulation of cholesterol in the dysfunctional lysosomes caused by these drugs leads to lysosomal membrane damage due to increased oxidative stress, resulting in the induction of lysosomal membrane permeabilization and the release of cathepsin B into the cytosol, which eventually promotes autophagy and cell death. Alkylphospholipids such as perifosine, edelfosine, erucylphosphocholine interfere with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum, hindering cholesterol esterification, Accumulation of unesterified cholesterol in the cell leads to autophagy, which inhibits the viability of GBM cells. SCP2 binds to cholesterol with high affinity and is involved in transporting cytoplasmic cholesterol to the plasma membrane. Itraconazole interferes with the transport of cholesterol from endosomes and lysosomes to the cell membrane by inhibiting the transcription of SCP2.