Ferroptosis-inhibiting natural products and their mode of action: Targeting Redox Signaling
Ferroptosis is a form of regulated cell death program with promising applications in treating pathologies characterized by excessive cell death, such as degenerative liver disease. The number of proteins involved in ferroptosis is growing, as is the number of small molecules that interfere with ferroptosis pathways. Challenges in targeting ferroptosis arise from interference with redox-dependent signalling cascades whose regulatory mechanisms, unlike kinase signalling cascades, are less studied and not fully understood. The development of drug candidates against ferroptosis is still in the early stages and many questions remain to be answered:
- What is the most effective strategy to prevent ferroptosis?
- Are there additional targets beyond the known anti-ferroptotic defense systems that are more suitable for efficient and prolonged inhibition of ferroptotic cell death in degenerative diseases?
- Can synergistic effects be achieved by targeting different nodes of ferroptotic signaling?
- Are the anti-ferroptotic compounds effective in protecting against liver degeneration in vivo?
Harnessing the enormous structural diversity of natural products could help to answer these questions, identify novel targets, and unravel molecular mechanisms.
Team: Solveigh Koeberle, Minh Bui Hoang, Loc Le-Xuan
Subprojects:
- Effects of redox regenerating systems and compounds on ferroptotic cell death
- Direct inhibition of membrane lipid peroxidation via non-radical scavenging mechanisms
- Differences in the cellular response patterns of NRF2 activators that provide protection against ferroptosis versus those that are unable to mitigate ferroptosis.
- Shaping the phospholipid composition by anti-ferroptotic compounds as novel mechanism for the treatment of degenerative liver disease.