Figure 1:

Illustration of the autophagy process including initiation, elongation, maturation, autophagosome fusion and degradation. Binding of RANKL to its receptor, RANK, activates TRAF3 degradation via the autophagy/lysosome system, which can be disrupted by eliglustat due to the prevention of lysosome degradation. Eliglustat blocks GSLs formation from ceramide by inhibiting GCS (encoded by UGCG), to reduce GlcCer, LacCer, gangliosides and other GSLs ([neo]lacto-series, globosides, isoglobosides). Specifically, gangliosides GD3 and GM2 support autophagy during initiation and maturation. In our study, we concluded that GlcCer and LacCer are essential components for lysosome degradation. Hence, blocking GlcCer and LacCer formation by eliglustat disrupts autophagy, and halts osteoclast formation and activation, in addition to its known roles in the treatment of Gaucher disease. Created with BioRender.com.