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Post-Translational Modification of GPX4 is a Promising Target for Treating Ferroptosis-Related Diseases
Can Cui1, Fei Yang2,3, Qian Li2,4,5
1School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Abstract:
Glutathione peroxidase 4 (GPX4) is one of the most important antioxidant enzymes. As the key regulator of ferroptosis, GPX4 has attracted considerable attention in the fields of cancer, cardiovascular, and neuroscience research in the past 10 years. How to regulate GPX4 activity has become a hot topic nowadays. GPX4 protein level is regulated transcriptionally by transcription factor SP2 or Nrf2. GPX4 activity can be upregulated by supplementing intracellular selenium or glutathione, and also be inhibited by ferroptosis inducers such as ML162 and RSL3. These regulatory mechanisms of GPX4 level/activity have already shown a great potential for treating ferroptosis-related diseases in preclinical studies, especially in cancer cells. Until recently, research show that GPX4 can undergo post-translational modifications (PTMs), such as ubiquitination, succination, phosphorylation, and glycosylation. PTMs of GPX4 affect the protein level/activity of GPX4, indicating that modifying these processes can be a potential therapy for treating ferroptosis-related diseases. This article summarizes the protein characteristics, enzyme properties, and PTMs of GPX4. It also provides a hypothetical idea for treating ferroptosis-related diseases by targeting the PTMs of GPX4.
Insights
Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, can be targeted through its post-translational modifications (PTMs) for disease treatment. Understanding GPX4 PTMs offers new therapeutic strategies for ferroptosis-related conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Cellular Biology
Background:
- Glutathione peroxidase 4 (GPX4) is a critical antioxidant enzyme and the primary regulator of ferroptosis.
- GPX4's role in cancer, cardiovascular, and neuroscience research has garnered significant attention.
- Regulation of GPX4 activity is a key area of therapeutic interest.
Purpose of the Study:
- To summarize GPX4 protein characteristics, enzyme properties, and post-translational modifications (PTMs).
- To explore the potential of targeting GPX4 PTMs for treating ferroptosis-related diseases.
Main Methods:
- Review of existing literature on GPX4 regulation, including transcriptional control and PTMs.
- Analysis of how PTMs like ubiquitination, succination, phosphorylation, and glycosylation impact GPX4 function.
- Synthesis of information to propose therapeutic strategies targeting GPX4 PTMs.
Main Results:
- GPX4 protein levels are regulated by transcription factors SP2 and Nrf2.
- GPX4 activity can be modulated by selenium/glutathione supplementation or ferroptosis inducers (ML162, RSL3).
- GPX4 undergoes various PTMs (ubiquitination, succination, phosphorylation, glycosylation) that influence its activity and stability.
Conclusions:
- GPX4 PTMs represent a novel and promising therapeutic avenue for ferroptosis-related diseases.
- Targeting GPX4 PTMs could offer new treatment strategies, particularly for cancer.
- Further research into GPX4 PTMs is warranted to develop effective therapies.
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