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NCOA4

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.

Recent Publications Focus

Below is a summary of the newest research publications targeting NCOA4 (sorted by publication date).

  • Gold(I)-loaded nanomedicine for liver cancer: A 2026 study in Journal of Medicinal Chemistry reported a closed-loop therapeutic strategy for liver cancer in which TEP NPs activated NCOA4-mediated ferritinophagy, leading to ferritin degradation and a surge in labile iron. This iron release was described as synergizing with TrxR inhibition to drive ferroptosis, supporting the use of ferritinophagy as a pro-death mechanism in cancer therapy.

  • M2 macrophage-induced ferroptosis resistance in glioblastoma: An integrative multi-omics and machine learning study in Functional & Integrative Genomics found that M2-polarized macrophages promoted ferroptosis resistance in glioblastoma cells by suppressing NCOA4 and increasing FTH1 expression. The resulting reduction in labile iron release was linked to decreased susceptibility to ferroptosis, highlighting NCOA4 as a mediator of microenvironment-driven iron handling in glioblastoma.

  • MARCH7 as a ferroptosis regulator: A Cell paper described MARCH7 as a “ferro-guardian” that protects against ferroptosis by ubiquitylating NCOA4 at Lys42 through K48-linked ubiquitination, thereby promoting proteasomal degradation of NCOA4 and reducing the labile iron pool. This work identified a post-translational mechanism controlling NCOA4 abundance and iron-dependent cell death.

  • PCSK9 and vascular smooth muscle cell ferroptosis: In Cell Proliferation, researchers studying abdominal aortic aneurysm progression reported that PCSK9 triggers ferritinophagy in vascular smooth muscle cells, with evidence including decreased FTH1 and NCOA4, an increased LC3-II/I ratio, and enhanced FTH1-LAMP1 colocalisation. The findings linked NCOA4-associated ferritinophagy to vascular cell ferroptosis and disease progression.

  • Pterostilbene in intervertebral disc degeneration: A Phytomedicine study showed that pterostilbene inhibits ferritinophagy-mediated ferroptosis through the NRF2/NCOA4/FTH1 axis and alleviates intervertebral disc degeneration via nanoliposomal delivery. This work positioned NCOA4 as part of an antioxidant-ferroptosis regulatory pathway relevant to degenerative tissue injury.

  • Dandelion extract in triple-negative breast cancer: A Journal of Ethnopharmacology publication reported that Taraxacum mongolicum extract suppresses triple-negative breast cancer by inducing ferroptosis via NCOA4-mediated ferritinophagy. The study supports the concept that natural products can exploit NCOA4-dependent iron mobilization to promote cancer cell death.

  • NCOA4 and micro-/nanoplastics-associated depressive-like behavior: A study in Chemico-Biological Interactions used integrative Mendelian randomization and single-cell transcriptomic data mining to identify NCOA4 as a central regulator linking ferroptosis to micro- and nanoplastics-induced depressive-like behavior. This suggests that NCOA4 may participate in iron-dependent neurobiological stress responses beyond cancer and classical inflammatory settings.

  • selenium nanoparticles in mastitis: In Journal of Dairy Science, selenium nanoparticles were reported to attenuate Klebsiella pneumoniae-induced mastitis in goats by suppressing NCOA4-mediated ferritinophagy, thereby reducing iron overload and lipid peroxidation. The study also noted reduced NCOA4–FTH1 colocalization, consistent with inhibition of ferritinophagic flux and ferroptosis.

Overall, these recent publications portray NCOA4 as a versatile regulator of ferritinophagy and iron release across diverse disease models, including cancer, vascular disease, degenerative disorders, infection-associated inflammation, and neurobehavioral phenotypes. Across the studies, NCOA4 was modulated by nanomedicine, natural compounds, nanoparticles, and ubiquitin-mediated degradation, with downstream effects converging on ferroptosis, FTH1, labile iron, and related pathways such as NRF2, GPX4, and PCSK9.

Result PMIDs

  • [PMID 42269711]
  • [PMID 41780848]

Target PMIDs

  • [PMID 42266061]
  • [PMID 42321379]
  • [PMID 42049018]
  • [PMID 41886954]
  • [PMID 41707813]
  • [PMID 41690538]
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