GPX4 in cell death, autophagy, and disease Original paper

What Was Studied?

The research paper reviewed the roles of GPX4 (Glutathione Peroxidase 4) in cell death, particularly focusing on its function in ferroptosis, autophagy, and disease. GPX4, a key selenoenzyme, plays a pivotal role in mitigating lipid peroxidation, thus protecting cells from oxidative stress and various forms of regulated cell death (RCD). The study explores GPX4’s different isoforms (cytosolic, mitochondrial, and nuclear), their distinct functions, and how mutations in GPX4 impact disease processes, particularly in cancer, neurodegeneration, and inflammation.

Who Was Reviewed?

The paper reviews existing studies on GPX4’s functions across different types of cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, and parthanatos). It also discusses the molecular mechanisms that underlie GPX4’s involvement in autophagy and its regulation of metabolic processes like lipid peroxidation. The paper reviews animal models, specifically mice with different GPX4 knockout or knockout variants, to understand its broader impact on health, including its roles in embryonic development, tumorigenesis, neurodegeneration, and immune system regulation.

Most Important Findings

GPX4 was found to play a critical role in multiple cell death pathways, especially ferroptosis, which is a form of non-apoptotic, iron-dependent cell death triggered by lipid peroxidation. The study emphasizes that the loss of GPX4 results in massive oxidative damage, leading to cellular dysfunction and death, which can exacerbate diseases like cancer, neurodegenerative disorders, and inflammation. The research also highlights the dual role of GPX4 in cancer: it can both prevent tumorigenesis by inhibiting ferroptosis and contribute to inflammation that supports tumor growth. Additionally, mutations in GPX4 (such as R152H) have been implicated in rare genetic diseases like Sedaghatian-type spinal metaphyseal dysplasia (SSMD).

The study discusses GPX4’s regulatory role in autophagy, particularly how autophagic degradation can influence its activity and ferroptosis. Autophagic pathways targeting GPX4, such as the role of TMEM164, and autophagy-mediated GPX4 degradation in response to oxidative stress, were also identified as significant. Furthermore, the research found that the proper functioning of GPX4 is essential for sperm development and male fertility, with deficits leading to infertility.

Greatest Implications

The findings of this review have significant implications for both therapeutic and diagnostic applications. Understanding GPX4’s diverse roles across different forms of cell death and its connection to diseases could lead to novel strategies for treating oxidative stress-related diseases. In cancer, for example, GPX4 inhibitors might enhance the efficacy of chemotherapy and radiotherapy by promoting ferroptosis. Conversely, enhancing GPX4 activity could be a therapeutic approach for diseases where ferroptosis is detrimental, such as neurodegenerative disorders. Moreover, GPX4’s involvement in immune responses suggests potential for targeting it to modulate inflammation and immune system dysfunction in diseases like autoimmune conditions and sepsis.