Ferroptosis and necroinflammation, a yet poorly explored link

Area of Science:

• Cellular Biology
• Immunology
• Pathology

Background:

• Ferroptosis is iron-dependent cell death marked by lipid peroxidation.
• It is implicated in pathologies such as ischemia/reperfusion injury, neurodegeneration, and cancer.
• Key pathways involve cysteine availability, glutathione (GSH) biosynthesis, and polyunsaturated fatty acid metabolism.

Purpose of the Study:

• To review the current understanding of the link between ferroptosis and necroinflammation.
• To discuss how ferroptosis may alert the innate immune system.
• To explore the roles of lipoxygenase (LOX) and prostaglandin-endoperoxide synthase (PTGS) in ferroptosis.

Main Methods:

• Literature review of ferroptosis and necroinflammation research.
• Analysis of the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis in ferroptosis.
• Examination of damage-associated molecular patterns (DAMPs) released during ferroptosis.

Main Results:

• Ferroptotic cells release pro-inflammatory DAMPs, activating the innate immune system.
• The GSH/GPX4 node influences LOX and PTGS activities, affecting the "peroxide tone."
• LOX and PTGS products may have dual roles in ferroptosis, acting both cell-autonomously and non-autonomously.

Conclusions:

• Ferroptosis is a significant contributor to organ damage in diseases like kidney and brain pathologies.
• The interplay between ferroptosis and necroinflammation involves complex signaling pathways.
• Further research into the early events sensitizing cells to ferroptosis is warranted to understand innate immune system activation.