Dihydroceramide desaturase 1 (DEGS1) (DEGS1)

Dihydroceramide desaturase 1 (DEGS1) is a key enzyme in the de novo sphingolipid synthesis pathway, responsible for converting dihydroceramide into ceramide by introducing a trans-4,5 double bond [1]. The 'ER stress / unfolded protein response pathway via dihydroceramide accumulation' describes the mechanism where DEGS1 inhibition leads to an increase in intracellular dihydroceramides, which act as signaling molecules to trigger the Unfolded Protein Response (UPR) [2]. This pathway primarily activates the PERK-eIF2α-ATF4-CHOP axis, which can induce cell cycle arrest, autophagy, or apoptosis depending on the cellular context [3]. The synthetic retinoid fenretinide (4-HPR) is a well-known inhibitor of DEGS1 that exploits this mechanism to promote cell death in various malignancies, including neuroblastoma and leukemia [3, 4]. Beyond oncology, DEGS1 is a target of interest in metabolic diseases, as dihydroceramide accumulation is strongly linked to insulin resistance and hepatic steatosis [2]. Therapeutic development targeting this pathway must balance the induction of stress in target cells with the potential for systemic metabolic disturbances or dermatological toxicities.

Other names

Sphingolipid delta(4)-desaturase DES1Degenerative spermatocyte homolog 1DES1DEGSDihydroceramide desaturase

Inhibition of DEGS1 leads to the accumulation of dihydroceramides, which triggers the PERK-eIF2α-ATF4-CHOP arm of the unfolded protein response (UPR), resulting in ER stress-mediated apoptosis or autophagy.