Ferroptosis in Toxicology: Present and Future

Abstract

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal mechanism in understanding the toxicological effects of various environmental pollutants. This short review delves into the intricate pathways of ferroptosis, its induction by diverse environmental toxicants, and the subsequent implications for human health. By elucidating and understanding pathways involved in environmental exposures and ferroptosis, we aim to shed light on potential therapeutic interventions and preventive strategies. Furthermore, identifications of biomarkers of ferroptosis will aid in monitoring ferroptosis-induced diseases/tissue damage, promoting the development of targeted therapies.

Keywords: PFAS; environmental pollutants; ferroptosis; heavy metals; pesticides.

Figure 1

Schematic representation of the ferroptosis pathway. Loss of iron homeostasis and depletion of glutathione (GSH), caused by inhibition of system Xc⁻ and glutathione peroxidase 4 (GPX4) by chemicals or pollutants, lead to increased reactive oxygen species (ROS) formation. This oxidative stress results in lipid peroxidation, culminating in ferroptotic cell death.

Figure 2

A schematic representation illustrating how environmental toxins—such as PFAS, heavy metals, and particulate matter—impact various cellular pathways that promote reactive oxygen species (ROS) generation, lipid peroxidation, and ultimately induce ferroptotic cell death in humans. Abbreviations: GCL (glutamate-cysteine ligase), GSS (glutathione synthetase), GPX4 (glutathione peroxidase 4), and RSL3 (Ras-selective lethal 3).