NCOA4

Overview

NCOA4 (nuclear receptor coactivator 4) is a gene encoding a protein best known for its central role in ferritinophagy, the selective autophagic degradation of ferritin. By promoting ferritin turnover, NCOA4 helps regulate intracellular iron availability and the labile iron pool, thereby influencing iron-dependent processes such as ferroptosis. In this context, NCOA4 is a key mediator linking cellular iron storage to oxidative stress and lipid peroxidation.

In biomedical research, NCOA4 is frequently studied as a regulator of disease-associated ferroptosis in cancer, inflammatory disorders, and degenerative conditions. Recent studies have examined how modulation of NCOA4 affects the NRF2/NCOA4/FTH1 axis, ferritin heavy chain 1 (FTH1) abundance, and downstream iron release, often in conjunction with pathways such as Nrf-2-SLC7A11-GSH and SIRT6/NRF2/GPX4 signaling.

Focus of Latest Publications

Recent publications have continued to position NCOA4 as a central regulator of ferritinophagy and ferroptosis across diverse disease contexts. In glioblastoma, integrative multi-omics and single-cell analyses linked ferroptosis-related genes with monocyte/macrophage infiltration, and mechanistic experiments showed that M2-polarized macrophages promoted ferroptosis resistance in tumor cells by suppressing NCOA4 and increasing FTH1 expression, thereby limiting labile iron release. This work identified an NCOA4-FTH1 axis through which the immune microenvironment can blunt the tumor-suppressive effects of the ferroptosis inducer erastin.

Several studies have explored therapeutic strategies that act through NCOA4-mediated ferritinophagy to promote ferroptosis. In liver cancer, a tumor-targeting gold(I)-loaded nanomedicine was reported to activate NCOA4-mediated ferritinophagy, causing ferritin degradation, increasing labile iron, and synergizing with thioredoxin reductase inhibition to drive ferroptosis, immunogenic cell death, and immune activation in vivo. In triple-negative breast cancer, dandelion extract was investigated as a ferroptosis-inducing agent via NCOA4-mediated ferritinophagy, while in intervertebral disc degeneration, pterostilbene was reported to inhibit ferritinophagy-mediated ferroptosis through the NRF2/NCOA4/FTH1 axis, with nanoliposomal delivery used to alleviate disease-related pathology.

Other recent work has highlighted NCOA4 as a node in ferroptosis suppression and in environmentally induced injury. A study of the E3 ubiquitin ligase MARCH7 showed that it directly ubiquitylates NCOA4, promoting its proteasomal degradation and reducing the labile iron pool, thereby suppressing ferroptosis. In a separate neurotoxicity model, environmentally realistic micro- and nanoplastics were found to induce depressive-like behaviors and neuronal damage through NCOA4-dependent ferritinophagy and ferroptosis associated with mitochondrial iron overload; pharmacological inhibition of autophagy reduced ferroptosis and improved neuronal survival. Together, these studies underscore NCOA4 as a key determinant of iron handling and ferroptotic sensitivity, with implications for cancer therapy, tissue protection, and toxicant-induced neurological injury.

Key Publications

Jun Integrative multi-omics analysis and machine learning identify M2 macrophage-induced ferroptosis resistance in glioblastoma. (Functional & integrative genomics, 2026, PMID 42321379): "Mechanistically, M2-polarized macrophages conferred ferroptosis resistance to GBM cells by suppressing NCOA4 and enhancing FTH1 expression, thereby reducing labile iron release."
Jun Gold(I)-Loaded Nanomedicine for Liver Cancer: A Closed-Loop Strategy Integrating Ferritinophagy-Driven Ferroptosis and Immunotherapy. (Journal of medicinal chemistry, 2026, PMID 42266061): "Simultaneously, TEP NPs activate NCOA4-mediated ferritinophagy, leading to ferritin degradation and a surge in labile iron that synergizes with TrxR inhibition to drive ferroptosis."
Jun Stabilizing MARCH7 as a ferro-guardian against ferroptosis. (Cell, 2026, PMID 42049018): "Mechanistically, MARCH7 ubiquitylates nuclear receptor coactivator 4 (NCOA4) at residue Lys42 by K48-linked ubiquitination, promoting NCOA4 proteasomal degradation and reducing the labile iron pool."
Jun Pterostilbene inhibits ferritinophagy-mediated ferroptosis via the NRF2/NCOA4/FTH1 axis and alleviates intervertebral disc degeneration through nanoliposomal delivery. (Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026, PMID 41886954): "Pterostilbene inhibits ferritinophagy-mediated ferroptosis via the NRF2/NCOA4/FTH1 axis and alleviates intervertebral disc degeneration through nanoliposomal delivery."
May Dandelion (Taraxacum mongolicum Hand. -Mazz.) extract inhibits triple-negative breast cancer by inducing ferroptosis via NCOA4-mediated ferritinophagy. (Journal of ethnopharmacology, 2026, PMID 41707813): "inducing ferroptosis via NCOA4-mediated ferritinophagy."
May Realistic-NPs trigger depression-like behaviors via mitochondrial iron overload mediating ferroptosis. (Chemico-biological interactions, 2026, PMID 41690538): "Integrative Mendelian randomization and single-cell transcriptomic data mining identified nuclear receptor coactivator 4 (NCOA4) as a central regulator linking ferroptosis to micro- and nanoplastics induced depressive-like behavior."