CYB561A3 encodes a transmembrane ferrireductase that functions as a critical regulator of cellular iron homeostasis and melanin production. The protein utilizes ascorbate as an electron donor in the cytoplasm to reduce Fe(3+) to Fe(2+) within late endosomes and lysosomes 1, facilitating iron mobilization to the cytoplasm via metal transporters. Beyond its canonical iron metabolism role, CYB561A3 represents a novel pigmentation regulator that impacts melanogenesis and oxidative phosphorylation pathways, contributing to skin color diversity across African populations 2. The gene shows evidence of local adaptation influencing human skin pigmentation variation 3. Clinically, CYB561A3 exhibits cell-type-specific dependencies: it is essential for Burkitt lymphoma cell proliferation and survival through its role in lysosomal iron reduction, with knockout causing profound iron starvation, catastrophic lysosomal and mitochondrial damage, and impaired respiration 1. Notably, CYB561A3 expression is significantly downregulated in HPV-induced warts compared to healthy skin 4, suggesting altered iron metabolism in viral infections. These findings establish CYB561A3 as both an evolutionary determinant of human skin pigmentation and a potentially attractive therapeutic target for Burkitt lymphoma.