Mechanistically, we identified 2 lipid pathways, the peroxisome/AGPS-driven EPL biosynthesis pathway, and the UGCG-catalyzed ceramide-to-GluCer pathway, that collaboratively regulate ceramide homeostasis and mediate drug tolerance in a subset of CD36+ persister cells and melanoma cells with acquired MAPKi resistance. The gene discussed is CD36; the disease is melanoma.