Sphingolipid metabolism enzymes as validated targets for overcoming tumor therapeutic resistance

Abstract

This work analyzes the mechanisms of tumor therapeutic resistance mediated by metabolic adaptations in the sphingolipid pathway. It describes the concept of the "sphingolipid rheostat," where a shift from pro-apoptotic ceramide to pro-survival sphingosine-1-phosphate (S1P) promotes cell survival under stress. The review highlights the key enzymes driving this shift—glucosylceramide synthase (GCS), acid ceramidase (AC), and sphingosine kinase 1 (SPHK1)—as validated therapeutic targets. It is demonstrated that pharmacological inhibition of these enzymes can restore tumor sensitivity to chemotherapy, targeted drugs, and immunotherapy, offering a promising strategy for overcoming multidrug resistance.