Nuclear receptor coactivator 4-mediated ferritinophagy pathway (NCOA4-mediated ferritinophagy)

The Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy pathway is a specialized autophagic process essential for maintaining cellular and systemic iron homeostasis (Santana-Codina & Mancias, 2018) [1]. In this pathway, NCOA4 acts as a selective cargo receptor that directly binds to the ferritin heavy chain 1 (FTH1) subunit of the ferritin complex and facilitates its transport to lysosomes for degradation (Mancias et al., 2014) [12]. This process, known as ferritinophagy, releases stored iron into the cytosolic labile iron pool, making it available for critical biological functions such as heme biosynthesis and mitochondrial respiration (Mancias et al., 2015) [12]. However, excessive activation of this pathway can lead to an overabundance of free iron, which catalyzes the production of reactive oxygen species via the Fenton reaction and triggers ferroptosis, an iron-dependent form of regulated cell death (Gao et al., 2016) [4, 8]. Consequently, the NCOA4-ferritin axis has emerged as a significant therapeutic target in oncology, where inducing ferritinophagy can sensitize resistant cancer cells to ferroptosis (Autophagy, 2026) [6, 7]. Conversely, in neurodegenerative diseases and ischemia-reperfusion injury, inhibiting this pathway may protect cells from iron-mediated oxidative damage and lipid peroxidation (Frontiers, 2019; PubMed, 2024) [4, 14]. Current pharmacological research explores NCOA4 degraders, iron chelators, and autophagy modulators to fine-tune this pathway for clinical benefit (Ji et al., 2024) [11].

Other names

FerritinophagyNCOA4-ferritin axisNCOA4-FTH1 axisFerritin-NCOA4 axisNCOA4-mediated selective autophagy

Modulation of iron release from ferritin via NCOA4-mediated lysosomal degradation to regulate the labile iron pool and ferroptosis sensitivity.