Ferroptosis as a New Type of Inflammatory Programmed Cell Death

When it comes to programmed cell death (PCD), apoptosis is usually the first process that comes to mind. However, there is a new type of inflammatory PCD discovered in 2012, known as ferroptosis, that is genetically and biochemically distinct from other PCD.¹

It is usually accompanied by a significant amount of iron accumulation and lipid peroxidation during the cell death process. Oxidative cell death occurs when there is a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) affected by the ferroptosis-inducing factors. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many conditions such as acute kidney injury, blood diseases, tumors, and neurological diseases.

Activating or blocking the ferroptosis pathway has proven to be a promising strategy to alleviate progression of numerous diseases. Therefore, the specific molecular mechanisms and functional changes of ferroptosis should be further examined for the development of related diseases. Let’s take a closer look at the main mechanisms of ferroptosis.

Mechanism of Ferroptosis

Morphologically, ferroptosis occurs mainly in cells as reduced mitochondrial volume, increased bilayer membrane density, and reduction or disappearance of mitochondrial cristae; but the cell membrane remains intact, the nucleus is normal in size, and there is no concentration of chromatin. Biologically, ferroptosis sensitivity is modulated by 4 main mechanisms:¹

A) The regulation of glutathione (GSH) and redox homeostasis, such as function of system x_c^-, glutathione peroxidase 4 (GPX4) regulation, FSP1-CoQ10- NAD(P)H pathway, sulfur transfer pathway, mevalonate (MVA) pathway, glutamine metabolic pathway, NRF2 and p53 regulatory axis.

B) The regulation of iron homeostasis, such as the regulation of ATG5-ATG7-NCOA4 pathway, IREB regulation system, and the regulatory pathways of heat shock proteins.

C) Related enzymes around glucose and lipid metabolism, such as PHGDH, G6PD, ACSL4, and LPCAT3, etc.

D) Mitochondria function regulation, such as voltage-dependent anion channels (VDACs), mitochondrial electron transport chain (ETC), TCA cycle, and glutaminolysis.

The most common regulation of ferroptosis is achieved through mechanism A above. System x_c^- provides the exchange of cysteine and glutamate in and out of the cell. Cysteine that is in the cells is involved in the synthesis of glutathione (GSH) and works to reduce ROS and reactive nitrogen together with GPX4. While P53 can inhibit the system x_c^- uptake of cysteine and RSL3 can inhibit GPX4, both inhibitions can lead to the accumulation of lipid ROS and eventually induce ferroptosis.²

After examining the mechanism and understanding the pathways involved in the process, it’s important to note that ABclonal offers several ferroptosis antibodies in our catalog, for use in multiple areas of research as shown in the table below:

Ferroptosis Research Products at ABclonal

**All product listed above have human, mouse and rat reactivity.

**Additional related antibodies not shown in the table above can be found here.

References

1. Li, Jie, et al. “Ferroptosis: Past, Present and Future.” Cell Death & Disease, vol. 11, no. 2, 2020, doi:10.1038/s41419-020-2298-2.
2. Cao, Jennifer Yinuo, and Scott J. Dixon. “Mechanisms of Ferroptosis.” Cellular and Molecular Life Sciences, vol. 73, no. 11-12, 2016, pp. 2195–2209., doi:10.1007/s00018-016-2194-1.