3-ketodihydrosphingosine reductase (KDSR)

3-ketodihydrosphingosine reductase (KDSR) is an oxidoreductase enzyme anchored in the endoplasmic reticulum membrane, with a catalytic domain facing the cytosol. It catalyzes the NADPH-dependent reduction of 3-ketodihydrosphingosine to dihydrosphingosine, the second essential step in de novo sphingolipid biosynthesis. Its activity is fundamental to the synthesis of ceramides and downstream sphingolipids, which regulate cell signaling, apoptosis, differentiation, and the maintenance of skin and ER integrity. Genetic mutations can cause skin disorders (erythrokeratodermia, keratoderma), liver injury, and cancer predisposition (e.g., leukemia, follicular lymphoma). The enzyme is weakly expressed in hematopoietic tissue but plays a critical role in cancer cell survival and normal skin/liver function. Disruption of KDSR drives ER stress, UPR dysregulation, and may be therapeutically relevant in diseases involving sphingolipid metabolism.

Other names

3-dehydrosphinganine reductasefollicular variant translocation protein 1 (FVT1)KDSR3KDS reductase

Drugs or genetic interventions targeting KDSR block conversion of 3-ketodihydrosphingosine to dihydrosphingosine, resulting in sphingolipid depletion and metabolic/ER stress. Combinatorial targeting with ER stress inducers can synergistically enhance leukemia cell death.