Redox-regenerative biogenic agents in ferroptosis

Liver diseases account for 3.5% of global deaths, with metabolic dysfunction-associated fatty liver disease (MAFLD) rapidly becoming the most prevalent form. MAFLD is driven by factors such as unhealthy lifestyles, obesity, insulin resistance, and genetic predisposition. Additionally, alcohol consumption, medications, and viral infections contribute significantly to liver-related mortality. Current treatment options are extremely limited, underscoring the urgent need for innovative therapies. Cell death is a natural and essential process in life. However, when it occurs in an uncontrolled or harmful way, it can contribute to diseases. One recently discovered form of cell death, ferroptosis, has been linked to degenerative liver disease. In these diseases, ferroptosis exacerbates the damage, especially in cell membranes that are rich in specific lipids. While traditional antioxidants may provide some relief, they have limitations, such as the risk of disrupting vital cellular processes when used over extended periods. Our research aims to better understand ferroptosis and develop new ways to prevent it, opening up exciting opportunities for innovative therapies. We focus on FSP1, a protein that protects cells against ferroptosis by activating compounds that neutralize harmful peroxidized lipids. What makes these compounds special is their ability to regenerate continuously, meaning that only very small amounts are needed to be effective. In addition, their activity is restricted to areas where FSP1 is present, potentially giving them enhanced intracellular specificity. This precise targeting could make these compounds safer and more effective than conventional antioxidants. Our goal is to deepen our understanding of how these compounds work, particularly in membrane regions where they are most needed inside the cell during ferroptosis. We are exploring the critical features that allow these compounds to function, the specific characteristics that support their interaction with FSP1, and the underlying reasons why minor structural changes can drastically alter their efficacy. We are also investigating how these compounds affect lipid composition, which provides insights into ferroptosis susceptibility. Finally, to translate our findings into practical treatments, we will evaluate these compounds in animal models of liver disease, including a nematode model of ferroptosis and a mouse model in which a key ferroptosis protector is removed, leading to severe liver damage. Our research has the potential to advance the treatment of degenerative liver diseases caused by ferroptotic cell death. By precisely targeting ferroptosis and requiring only low doses, compounds being regenerated by FSP1 could provide a significant alternative to current therapies for degenerative liver disease and improve outcomes for patients suffering from these challenging conditions.