New insights into the role of CYP26 in retinoic acid clearance.

INTRODUCTION All‑trans‑retinoic acid orchestrates vertebrate development and adult tissue homeostasis. Because both deficiency and excess are deleterious, atRA concentrations must be precisely controlled, making its local clearance essential. The cytochrome P450 family members CYP26A1/B1/C1 are the principal high‑affinity retinoic acid hydroxylases that terminate signaling and sculpt RA concentration gradients necessary for physiological homeostasis. Their inducibility by RA creates negative feedback whereby increased RA enhances its own clearance, shaping RA pharmacokinetics. AREAS COVERED Based on manual literature searching, this review integrates advances in CYP26 genetics, tissue expression, enzymology, and intracellular RA partitioning, and evaluates evidence linking CYP26 regulation to epithelial barrier biology, hepatic retinoid metabolism and disease, cancer stemness, musculoskeletal inflammation, and central nervous system retinoid homeostasis. Inhibitor discovery developments, including isoform-selective CYP26 inhibitors, are discussed, alongside therapeutic opportunities in dermatology, oncology, osteoarthritis, and CNS disorders. EXPERT OPINION CYP26 enzymes are underexploited therapeutic targets and gatekeepers of RA homeostasis. Promising avenues include topical and CYP26B1-preferential inhibition for keratinization disorders, exposure‑controlled combinations of atRA with RA-metabolism‑blocking agents in oncology and strategies that elevate endogenous RA signaling in inflammatory diseases. Progress will depend on biomarkers of RA exposure, improved isoform, and tissue selectivity, and trial designs that incorporate RA auto‑induction and metabolic variability.