Review highlights unique characteristics and mechanisms of ferroptosis

Frontiers JournalsJul 14 2024

Junxia Min, Fudi Wang, et al., at Zhejiang University School of Medicine, China, provided an in-depth review on the programmed cell death known as ferroptosis, which is driven by iron-dependent lipid peroxidation. The review highlights the unique characteristics and mechanisms of ferroptosis, distinguishing it from other forms of regulated cell death such as apoptosis, necroptosis, and pyroptosis. It underscores the role of ferroptosis in the pathogenesis of various diseases, including cancers, neurodegenerative disorders, cardiovascular diseases, and more.

Ferroptosis is characterized by the accumulation of reactive oxygen species (ROS) and the peroxidation of polyunsaturated fatty acids (PUFAs) in the presence of iron. This process is distinct because it does not require caspase activation or ATP and can be inhibited by iron chelators like deferoxamine (DFO). The review discusses the intricate molecular pathways involved in ferroptosis, such as the regulation of lipid peroxidation, the antioxidant system, and iron metabolism. It emphasizes the importance of the GPX4-GSH system in inhibiting lipid peroxidation and the role of ACSL4 and LPCAT3 enzymes in the metabolism and incorporation of PUFAs into membrane lipids.

The article further explores the implications of ferroptosis in human diseases, suggesting that it could be a potential target for clinical therapy. It details the involvement of ferroptosis in several diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and various cancers, where it has been observed to play a role in tumor growth and response to therapy. The review also discusses the potential of ferroptosis induction as a strategy in cancer treatment, given its ability to overcome resistance to conventional chemotherapies.

In terms of clinical applications, the review points out the need for specific biomarkers for diagnosing ferroptosis in clinical settings and the necessity of understanding the optimal conditions for the application of ferroptosis inducers or inhibitors. It also stresses the importance of selective targeting of ferroptosis in different cell types and tissues, depending on the disease context, to maximize therapeutic benefits and minimize side effects.

The authors conclude by noting that while significant progress has been made in understanding ferroptosis, there are still many open questions and challenges ahead. These include identifying the ultimate executors of ferroptosis post-lipid peroxidation, understanding the full spectrum of its molecular mechanisms, and translating these findings into effective clinical treatments. The review calls for more preclinical and clinical trials to validate the role of ferroptosis in human health and disease.