What question did this study set out to answer?

The review aims to explore the mechanisms of ferritinophagy and its implications in cancer therapy through targeting NCOA4.

April 13, 2026

NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology

Key Points

The review aims to explore the mechanisms of ferritinophagy and its implications in cancer therapy through targeting NCOA4.
Review of molecular mechanisms involved in ferritinophagy
Discussion of NCOA4's regulatory network, including transcription factors and post-translational modifications
Analysis of compounds inducing ferroptosis via the NCOA4-ferritinophagy pathway
NCOA4 is identified as the main receptor for ferritin degradation in lysosomes.
Ferritinophagy promotes ferroptosis, which can be leveraged for cancer therapy.
Natural compounds and repurposed drugs activating this pathway show potential in overcoming therapeutic resistance.

Abstract

Iron is vital for life but can be toxic in excess by forming reactive oxygen species. Ferroptosis, a type of regulated cell death, relies on iron-dependent lipid peroxidation and requires a labile iron pool (LIP) in cells. Ferritin stores iron safely, and its degradation increases the LIP. Ferritinophagy, the autophagic breakdown of ferritin, is crucial for releasing stored iron to trigger ferroptosis. This review examines ferritinophagy's molecular mechanisms, highlighting NCOA4 (nuclear receptor coactivator 4) as the main receptor targeting ferritin for lysosomal degradation. It also discusses the regulatory network controlling NCOA4, including transcriptional factors like TP53/p53 and MYC/c-Myc, RNA-binding proteins, and post-translational modifications such as ubiquitination. We explore ferritinophagy-induced ferroptosis as a promising anti-cancer approach. Research shows that various natural compounds, repurposed drugs, and new metal complexes can induce tumor cell death by activating the NCOA4-ferritinophagy pathway, which is crucial for overcoming therapeutic resistance in many cancers. Understanding this pathway highlights the relationship between iron metabolism, macroautophagy/autophagy, and cell death, offering a foundation for new treatments for cancer and iron-related diseases.Abbreviation: FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSH: glutathione; HIF: hypoxia-inducible factor; LIP: labile iron pool; MAPK/JNK: mitogen-activated protein kinase; NCOA4: nuclear receptor coactivator 4; PUFAs: polyunsaturated fatty acids; SLC7A11: solute carrier family 7 member 11; TFRC: transferrin receptor; TFEB: transcription factor EB.

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