Nuclear receptor coactivator 4 (NCOA4)

Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor involved in the autophagic degradation of ferritin (the main iron storage complex in cells), a process termed ferritinophagy[1][3][4]. Through this function, NCOA4 maintains intracellular and systemic iron homeostasis and is required for critical physiological processes such as erythropoiesis (red cell development)[3][4]. Molecularly, NCOA4 delivers ferritin to autophagosomes for lysosomal degradation; its abundance and activity are regulated by both autophagy and the ubiquitin-proteasome system, particularly through the E3 ligase HERC2 in an iron-dependent manner[1][3]. Loss of NCOA4 activity results in impaired iron mobilization, ferritin and iron accumulation in tissues, and anemia[2][3]. Beyond its physiological roles, NCOA4-mediated ferritinophagy has been implicated in cell sensitivity to ferroptosis, an iron-dependent and non-apoptotic cell death pathway relevant to cancer and neurodegenerative diseases[4]. There are currently no drugs directly targeting NCOA4 clinically, but modulation of its pathway is a proposed therapeutic strategy in diseases of iron overload, anemia, and ferroptosis-related conditions[4].

Other names

ARA70ELE1RFGNCoA-470 kDa AR-activator70 kDa androgen receptor coactivatorPTC3DKFZp762E1112androgen receptor-associated protein of 70 kDaferritin cargo receptor NCOA4ret fusedRet-activating protein ELE1RET-activating gene ELE1

Mediation of ferritin degradation by selective autophagy (ferritinophagy); Regulation of iron release from ferritin; Modulation of susceptibility to ferroptosis by controlling iron availability