KDSR (3-ketodihydrosphingosine reductase) is a critical endoplasmic reticulum enzyme that catalyzes the reduction of 3-ketodihydrosphingosine to sphinganine, the second step of de novo sphingolipid biosynthesis 1. This enzymatic function is essential for producing ceramides and other sphingolipids required for membrane trafficking, cell differentiation, and protein homeostasis 2. Loss-of-function KDSR mutations disrupt cellular ceramide synthesis and trigger compensatory activation of the sphingolipid salvage pathway, leading to accumulation of sphingosine and sphingosine 1-phosphate 1. This metabolic dysregulation causes ER stress, oxidative stress, and mitochondrial dysfunction 12. Biallelic KDSR mutations cause erythrokeratodermia variabilis et progressiva-4 (EKVP-4), characterized by hyperkeratotic plaques and progressive erythema 3. The disorder manifests as a spectrum of keratinization disorders ranging from palmoplantar keratoderma to generalized ichthyosis, frequently accompanied by thrombocytopenia due to impaired proplatelet formation in megakaryocytes 45. Additional manifestations include hepatic injury, steatosis, and megakaryocyte dysplasia 16. KDSR dysfunction also holds therapeutic potential in leukemia, where KDSR suppression combined with ER-stress induction shows synergistic effects 2.