HMOX2 (heme oxygenase 2) catalyzes the oxidative cleavage of heme at the alpha-methene bridge, releasing carbon monoxide, biliverdin, and ferrous iron 1. This enzyme plays critical roles in heme catabolism and cellular responses to oxidative stress and hypoxia 2. Mechanistically, HMOX2 functions downstream of major hypoxic pathway regulators. In Tibetan populations, HMOX2 variants show evidence of positive selection and male-specific associations with hemoglobin levels, suggesting the enzyme modifies high-altitude adaptation by regulating heme breakdown and maintaining relatively low hemoglobin levels 3. Disease relevance spans multiple conditions. HMOX2 is associated with migraine susceptibility, specifically identified as a risk variant for migraine with aura 4. It was identified as a novel candidate gene in late-onset Parkinson's disease, with rare deleterious variants showing significant excess in affected individuals 5. In cancer biology, HMOX2 serves as a biomarker for tumor-initiating cells (TICs) in lung tumors and is therapeutically targetable, with selective HMOX2 inhibition reducing tumor growth and increasing survival 6. Additionally, HMOX2 contributes to melanosphere formation in melanoma through B-Raf-dependent mechanisms 7. Clinically, HMOX2 represents a promising therapeutic target for cancer treatment, particularly for therapy-resistant TICs 8, and understanding its variants may inform personalized approaches to migraine and neurodegenerative disease management.