CYP2D6 is a hepatic cytochrome P450 monooxygenase that catalyzes the oxidative metabolism of approximately 20-25% of commonly used medications, including antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants 1. The enzyme uses molecular oxygen to insert one atom into substrates while reducing the second to water, with electrons provided by NADPH via cytochrome P450 reductase [UniProt sources]. Beyond drug metabolism, CYP2D6 catalyzes epoxidation of polyunsaturated fatty acids [UniProt sources], metabolizes the endocannabinoid anandamide to bioactive epoxyeicosatrienoic acid ethanolamides [UniProt sources], and converts cholesterol to 25-hydroxycholesterol for cellular homeostasis [UniProt sources]. CYP2D6 exhibits pronounced interindividual variability in expression and activity due to genetic polymorphism, with approximately 7% of Caucasians and 1% of Asians classified as poor metabolizers 2. This genetic variation significantly impacts drug pharmacokinetics and therapeutic outcomes 1. Beyond CYP2D6 gene polymorphisms, recent genome-wide association studies identified novel cis- and trans-genetic variants (rs1807493, rs1062753, rs4073010, rs729559) that independently regulate CYP2D6 expression and activity 1. Transcriptional regulation by factors such as small heterodimer partner and Krüppel-like factor 9 further contributes to variability 3. Understanding CYP2D6 genetic and transcriptional regulation is essential for precision medicine and optimizing drug therapy while preventing toxicity 2.