Sphingolipid metabolism dysregulation: A cause for lung cancer development, progression, and resistance to therapies

Lung cancer remains a leading cause of cancer-related mortality worldwide. Sphingolipids, a diverse class of lipids featuring a sphingoid base backbone, play essential roles in cellular processes and membrane structure. Complex sphingolipids such as sphingomyelins and glycosphingolipids maintain membrane integrity, while their metabolites—ceramide, sphingosine, and their phosphorylated forms, ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P)—act as bioactive lipids involved in regulating key cellular functions. Ceramide and sphingosine are generally tumor-suppressive, promoting apoptosis and inhibiting cell proliferation, whereas C1P and S1P support tumor progression through enhanced cell survival, proliferation, angiogenesis, and metastasis. S1P exerts its effects via G protein-coupled S1P receptors (S1PRs) and intracellular pathways, while C1P acts primarily through intracellular signaling. Dysregulation of these metabolites contributes to lung cancer pathogenesis, influencing tumor survival and resistance to therapy. Targeting sphingolipid metabolism—either by enhancing ceramide and sphingosine levels or inhibiting C1P and S1P—has shown promise in preclinical models. Moreover, these sphingolipid metabolites hold potential as biomarkers for diagnosis and prognosis in lung cancer. This review explores the roles of sphingolipids in lung cancer biology, their impact on tumor progression, and their therapeutic potential.