NCOA4 (nuclear receptor coactivator 4) functions primarily as a selective cargo receptor mediating ferritinophagy, the autophagic degradation of ferritin iron storage complexes 1. NCOA4 delivers ferritin to autolysosomes via interaction with ATG8 proteins, releasing bioavailable iron to maintain cellular iron homeostasis 1. This ferritinophagy process is essential for iron-dependent physiological functions including erythropoiesis 2. Mechanistically, NCOA4-mediated ferritinophagy is tightly coupled to ferroptosis, an iron-dependent form of regulated cell death 3. NCOA4 knockout cells show impaired ferritin degradation, reduced intracellular labile iron pools, and decreased ferroptosis sensitivity 4, whereas NCOA4 overexpression enhances ferroptosis 3. NCOA4 protein levels are regulated by ubiquitin ligase HERC2 downstream of NRF2, which controls iron homeostasis 5. Clinically, NCOA4-mediated ferritinophagy dysregulation has disease relevance in cancer and neurodegeneration 2. NCOA4 elevation promotes ferroptosis sensitivity in triple-negative breast cancer when combined with ferroptosis inducers 6, and contributes to atherosclerotic endothelial inflammation through ferroptosis 7. Conversely, disrupting NCOA4-ferritin interactions protects against ferroptosis-mediated acute kidney injury 8. Thus, modulating NCOA4-mediated ferritinophagy represents a therapeutic strategy for diseases involving ferroptosis dysregulation.