Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma
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Updated: Dec 30, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Yongfei Yang1,2, Meiying Luo3,4, Kexin Zhang3
1Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China. yangyf@bit.edu.cn.
Abstract:
Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.
Insights
Nedd4 protein degradation of VDAC2/3 channels increases cancer cell resistance to ferroptosis activator erastin. Depleting Nedd4 enhances erastin sensitivity, offering insights into overcoming drug resistance.
Area of Science:
- Cell Biology
- Biochemistry
- Oncology
Background:
- Ferroptosis is iron-dependent cell death marked by lipid hydroperoxide buildup.
- Erastin, a ferroptosis activator, targets voltage-dependent anion channels (VDAC2/3).
- Erastin treatment can paradoxically lead to VDAC2/3 degradation, suggesting resistance mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanism behind erastin-induced cellular resistance.
- To identify key regulators involved in VDAC2/3 degradation following erastin treatment.
- To explore strategies for overcoming drug resistance in ferroptosis-inducing cancer therapies.
Main Methods:
- Investigated the role of Nedd4 in erastin-treated cells.
- Analyzed VDAC2/3 protein levels and ubiquitination status.
- Assessed cancer cell sensitivity to erastin upon Nedd4 depletion.
Main Results:
- Erastin treatment induces Nedd4 expression.
- Nedd4 mediates ubiquitination and degradation of VDAC2/3 channels.
- Nedd4 depletion prevents VDAC2/3 degradation, increasing erastin sensitivity in cancer cells.
- A FOXM1-Nedd4-VDAC2/3 negative feedback loop was identified.
Conclusions:
- Nedd4 is a key mediator of erastin resistance by degrading VDAC2/3 channels.
- Targeting the FOXM1-Nedd4-VDAC2/3 axis may overcome erastin resistance in cancer.
- Understanding cellular adaptation to ferroptosis activators is crucial for therapeutic development.
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