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Updated: Sep 8, 2025
09:21
Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts
Published on: February 23, 2024
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TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy
Pandian Nagakannan1, Md Imamul Islam2, Shakila Sultana2
1Department of Physiology and Pathophysiology, University of Manitoba, Health Sciences Centre, Winnipeg, Canada; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Biochimica Et Biophysica Acta. Molecular Cell Research
|September 6, 2025
Summary
Thioredoxin-Inhibiting Protein (TXNIP) drives ferroptosis, a cell death pathway implicated in diseases. Inhibiting TXNIP may offer new therapeutic strategies for conditions involving ferroptosis.
Area of Science:
- Cellular biology
- Biochemistry
- Pathology
Background:
- Ferroptosis is an iron-dependent cell death characterized by lipid peroxidation.
- This cell death pathway is linked to various diseases, including cancer and neurodegeneration.
- Glutamate exposure can induce ferroptosis in neurons.
Purpose of the Study:
- To investigate the mechanisms of glutamate-induced ferroptosis in HT22 neurons.
- To determine the role of Thioredoxin-Inhibiting Protein (TXNIP) in ferroptosis.
- To explore TXNIP's potential as a therapeutic target.
Main Methods:
- Genetic manipulation of TXNIP (deletion and overexpression) in HT22 neurons, mouse embryonic fibroblasts, and Hela cells.
- Treatment with ferroptosis-inducing agents (erastin, RSL3, ML210).
- Assessment of cell viability, mitochondrial function, glutathione (GSH) and GPX4 levels, and ferritinophagy.
Main Results:
- TXNIP deletion conferred resistance to ferroptosis-inducing agents.
- TXNIP overexpression increased susceptibility to ferroptosis.
- TXNIP mediated ferroptosis by promoting ferritin degradation via NCOA4-mediated ferritinophagy, increasing labile iron and lipid peroxidation.
- TXNIP deletion protected against mitochondrial dysfunction independent of GSH and GPX4.
Conclusions:
- TXNIP is a key positive regulator of ferroptosis.
- TXNIP modulates ferroptosis by controlling iron availability through ferritinophagy.
- Targeting TXNIP presents a potential therapeutic strategy for ferroptosis-related diseases.
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