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Updated: May 26, 2025

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Published on: February 23, 2024

Autophagy induced by mechanical stress sensitizes cells to ferroptosis by NCOA4-FTH1 axis.

Chenyu Luo^1,2, Haisheng Liang¹, Mintao Ji¹

¹State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou, China.

|February 23, 2025

Summary

Tumor mechanics regulate iron metabolism and ferroptosis sensitivity. Reduced mechanical tension increases ferritin heavy chain 1 (FTH1) expression and decreases nuclear receptor coactivator 4 (NCOA4), conferring resistance to ferroptosis.

Keywords:

Ferritinophagy ferroptosis iron metabolism mechanotransduction phase separation

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Area of Science:

Cell death mechanisms
Cancer biology
Biophysics

Background:

Ferroptosis, an iron-dependent cell death, is crucial in diseases like cancer.
The extracellular matrix's mechanical properties influence tumor progression but their role in ferroptosis is unclear.

Purpose of the Study:

To investigate the impact of mechanical tension on ferroptosis.
To elucidate the underlying molecular mechanisms linking mechanics to ferroptosis.

Main Methods:

Cell culture under varying mechanical tension.
Analysis of ferritin heavy chain 1 (FTH1) and nuclear receptor coactivator 4 (NCOA4) expression.
Investigation of ferritinophagy and autophagy pathways.

Main Results:

Heightened mechanical tension sensitizes cells to ferroptosis.
Decreased mechanical tension confers resistance by enhancing FTH1 expression and reducing NCOA4.
Targeting NCOA4 rescues ferroptosis susceptibility under low mechanical tension.

Conclusions:

Mechanical cues from the tumor microenvironment regulate iron metabolism and ferroptosis.
The NCOA4-FTH1 axis and autophagy are key mediators of this regulation.
Targeting these pathways offers potential therapeutic strategies for ferroptosis-associated diseases.