ArticleJournal of advanced research2026
NCOA4-Mediated Ferritinophagy Induces Ferroptosis and Enriches Ferritin-Containing EVs via Ferritin Phase Separation to Promote Mechanical Ventilation-Induced Pulmonary Fibrosis.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- HIV Tat-Stimulated Microglial Extracellular Vesicles Are Enriched for Ferroptosis Mediators: Role of Dysregulated Autophagy.Journal of extracellular biology · 2026Article
- Ferritinophagy: molecular mechanisms and its crosstalk with ferroptosis in chronic respiratory diseases.Cell biology and toxicology · 2026Review
- NCOA4 as a regulatory switch linking DNA damage to lipid peroxidation in radiation response.Frontiers in cell and developmental biology · 2026Review
- Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.Frontiers in cell and developmental biology · 2026Review
- Ferroptosis in smoke inhalation injury: from mechanisms to potential therapeutic targets.Frontiers in cell and developmental biology · 2026Review
- Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities.Frontiers in immunology · 2026Review
- Ferroptosis in multiple myeloma: molecular mechanisms and therapeutic opportunities.Frontiers in oncology · 2026Review
- Regulated cell death in cancer: Mechanisms, crosstalk, and opportunities for therapy.Cancer letters · 2025Review
- NCOA4 and ferritinophagy in hematological malignancies: a double-edged regulator of iron metabolism and cell fate.Frontiers in oncology · 2025Review
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Authors and funding
12 authors.
Funding
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Abstract
introductionMechanical ventilation (MV) is essential for treating respiratory failure but can paradoxically lead to pulmonary fibrosis. The mechanisms of MV-induced pulmonary fibrosis (MVPF) remain poorly understood. Ferritinophagy, a novel autophagic process, regulates ferroptosis and the release of ferritin-containing extracellular vesicles (EVs), both of which may contribute to MVPF.
objectivesThis study aimed to investigate the mechanism of ferritinophagy, as well as how ferritin-containing EVs contribute to intercellular communication during MVPF progression.
methodsA mouse MVPF model was established using high tidal volume ventilation. Lung tissues were analyzed via single-cell RNA sequencing (scRNA-seq). Mechanical stretch (MS) was applied to alveolar epithelial cells (AECs) in vitro. Fluorescence recovery after photobleaching (FRAP) analysis was used to capture ferritin phase separation in live cells. Ferritinophagy and ferroptosis were assessed via key molecular markers. Chloroquine and AAV-mediated knockdown of AGTR1 and NCOA4 were used to inhibit ferritinophagy. EVs were isolated by ultracentrifugation and evaluated by immunoblotting and uptake assays.
resultsscRNA-seq revealed iron metabolism dysregulation and downregulation of ferroptosis-suppressor genes (Gpx4 and Fth) in AECs after MV. The ANG II/AGTR1 axis initiated ferritinophagy, leading to iron overload and subsequent ferroptosis. NCOA4-mediated ferritin phase separation under MS promoted ferritinophagy in AECs.Inhibition of ferritinophagy effectively reduced ferroptosis and alleviated MVPF. Moreover, ferritin-containing EVs released from injured AECs due to ferritinophagy can be assimilated by fibroblasts, resulting in fibroblast activation and extracellular matrix (ECM) accumulation through iron overload.
conclusionMV induces ANG II/AGTR1-mediated ferritinophagy and ferroptosis in AECs. NCOA4-driven ferritin phase separation promotes ferritinophagy under mechanical stress. Ferritin-containing EVs from damaged AECs activate fibroblasts, exacerbating MVPF. Our findings underscore the pivotal role of iron metabolism dysregulation in biomechanically induced programmed cell death and intercellular communication, and reveal potential therapeutic targets for the prevention and treatment of MVPF.
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