CYP26B1 is a cytochrome P450 monooxygenase that catalyzes the catabolism of retinoic acid (RA), the active metabolite of vitamin A, through 4-hydroxylation and oxidative metabolism 1. The enzyme also metabolizes xenobiotics including tazarotenic acid 2. CYP26B1 functions as a spatial regulator of RA signaling by limiting RA exposure in specific tissues; in the developing prefrontal cortex, CYP26B1 is upregulated in motor cortex regions to confine RA signaling to prospective prefrontal areas, thereby controlling cortical patterning, thalamic connectivity, and dendritic spine development 3. Loss-of-function mutations in CYP26B1 impair RA catabolism, leading to excessive RA accumulation with severe skeletal consequences including intrauterine fractures, femur angulation, and abnormal bone remodeling mediated through VEGFA overexpression and disrupted bone marrow vasculature 4. CYP26B1 mutations also predispose to lymphatic malformations by disrupting lymphangiogenesis through RA imbalance 5. Clinically, CYP26B1 inhibition represents a therapeutic strategy for keratinization disorders. The selective CYP26B1 inhibitor DX314 potentiates retinoid effects in ichthyosis and Darier disease while unexpectedly protecting epidermal barrier integrity 6. Dysregulation of CYP26-mediated RA metabolism also influences colorectal cancer ATRA sensitivity 7.