Ferroptosis-molecular mechanisms and newer insights into some diseases

Abstract

Ferroptosis is a recently discovered iron dependent form of programmed cell death, characterized by accumulation of lipid reactive oxygen species (ROS). It shows a strikingly different set of morphological characteristics from other forms of cell death, like reduced mitochondrial volume, increased bi-layer membrane density, and reduction of mitochondrial cristae with absence of any nuclear changes. Ferroptosis is mainly regulated by two core biochemical processes, namely iron accumulation and lipid peroxidation. Lipid peroxides exert their toxic effects by disturbing the integrity, structure and composition of bi-lipid cell membranes. However, being highly reactive compounds, they further propagate the generation of ROS, leading to cross-linking of DNA and proteins. Key regulators of ferroptosis include various genes involved in the above pathways, inhibition of the antioxidant system and upregulation of the oxidant system. Recent studies have shown the ferroptotic pathway to be involved in the patho-physiology of many diseases, including cancer. Understanding the biochemical mechanisms and key substances upregulating/inhibiting this pathway, may have an implication towards development of targeted therapies for various cancers, and, hence, has become a hotspot for biomedical research. This review article summarizes the core biochemical processes involved in ferroptosis, with a brief summary of its role in various diseases and possible therapeutic targets.