DiaSulFer
Targeting Ferroptosis in diabetes and diabetic complications by hydrogen (per)sulfide
DiaSulFer is exploring a new approach in the prevention and treatment of type 1 diabetes by suppressing a newly discovered type of iron-dependent cell death called ferroptosis, through the use of specific natural and synthetic hydrogen (per)sulfide donors. We aimed to examine whether such an approach will preserving the functional population of pancreatic β-cells, the key cells for insulin production, as well as the function of cells in tissues affected by diabetes.
Diabetes is a complex metabolic disorder characterized by elevated blood glucose levels caused by the lack/defect in insulin action, leading to changes in the metabolism of carbohydrates, lipids, and proteins. Uncontrolled hyperglycemia over time leads to the development of diabetic complications, increasing the risk of premature death. Incidence of diabetes is rising in epidemic proportions worldwide. It is particularly concerning that the International Diabetes Federation estimated that without interventions to stop the increase in diabetes, there will be at least 629 million people living with this disease by 2045. This alarming rise in diabetes incidence underscores the urgent need for new therapeutic approaches to effectively manage this condition.
At the core of the onset and progression of both diabetes type 1 and type 2 is the process of cell death, as it is involved in failure of pancreatic β cells, crucial for insulin production, as well as the cells in tissues affected by diabetic complications. Therefore, one of the greatest efforts in diabetes treatment today, as well as the main goal of DiaSulFer project, is to find approaches to prevent cell death and consequently the deterioration of tissues affected by diabetes.
Besides apoptosis and necrosis, which have been in the focus of extensive research for decades, our team has recently demonstrated the involvement of ferroptosis, a newly defined type of iron-dependent cell death, in the demise of cells in diabetes and diabetic pathologies. This discovery has enabled us to develop a new approach for the prevention and therapy of this condition, based on inhibiting the process of ferroptosis. For this purpose, DiaSulFer project will use specific natural and synthetic hydrogen sulfide (H2S) donors. Originally considered a toxic gas, H2S is now recognized as a gasotransmitter, and its reactive metabolites (RSS), primarily persulfides and polysulfides, represent redox signaling molecules that regulate important (patho)physiological processes through post-translational protein modification – persulfidation. Various natural and synthetic H2S/RSS donors therefore represent not only important research tools, but are also potent therapeutic agents.
Therefore, the overall objective of DiaSulFer is to identify the potential of novel approaches in prevention and control of type 1 diabetes using the specific H2S-related reactive compounds based on the physiologically relevant suppression of ferroptosis, and bring them to clinical application through following specific research objectives:
RO1: To reveal synthetic H2S/RSS donor with the best anti-ferroptotic potential in T1D.
RO2: To investigate mechanisms of the selected H2S/RSS donors’ anti-ferroptotic action and correlate them to the remodeling of protein persufidation in T1D – a preclinical study.
RO3: To test the antidiabetic effects of natural H2S/RSS donor in T1D patients from the aspects of anti-ferroptotic action and targeted protein persulfidation.
- DiaSulfer Project.
- DiaSulfer Project.
- DiaSulfer Project.
- DiaSulfer Project.
- DiaSulfer Project.
Ferroptosis:
Unraveling the Intricacies of Iron-Dependent Cell Death
Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation, distinct from other programmed cell death mechanisms such as apoptosis or necrosis with respect to the biochemical pathways, the main triggers and executors, and morphological features. Discovered relatively recently, ferroptosis has emerged as a crucial process in various physiological and pathological conditions. The term “ferroptosis” was first coined in 2012 to describe a distinct form of cell death induced by erastin, a small molecule compound that selectively targets oncogenic RAS-mutant cancer cells. Further studies have revealed that ferroptosis is primarily driven by the dysregulation of iron metabolism and lipid peroxidation. Specifically, the accumulation of intracellular iron catalyzes the Fenton reaction, leading to the production of reactive oxygen species (ROS) and subsequent oxidative damage to cellular membranes, particularly phospholipids containing polyunsaturated fatty acids (PUFAs). This lipid peroxidation cascade ultimately culminates in membrane rupture and cell death.
Several key players orchestrate the intricate machinery of ferroptosis regulation:
Iron Metabolism: Iron is a central player in ferroptosis, as its dysregulation, particularly excess intracellular iron, fuels the Fenton reaction and ROS production. Iron regulatory proteins such as ferritin, transferrin, and ferroportin tightly control cellular iron levels and influence ferroptotic susceptibility. Thus, the imbalance of intracellular iron homeostasis in favor of iron overload is pivotal in the induction of ferroptosis.
Lipid Peroxidation Machinery: Enzymes involved in lipid metabolism, such as lipoxygenases (LOXs) and acyl-CoA synthetase long-chain family member 4 (ACSL4), play critical roles in driving lipid peroxidation and promoting ferroptotic cell death. ACSL4 facilitates the incorporation of PUFAs into phospholipids, rendering cells more susceptible to oxidative damage.
Glutathione (GSH) and Glutathione Peroxidase 4 (GPX4): GSH, a potent antioxidant, acts as a crucial defense mechanism against ferroptosis acting as a cofactor for the specific membrane-associated isoform of the GSH-dependent peroxidase, GPX4. Selenoprotein GPX4 is the main lipid peroxides-scavenging enzyme that catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols, thereby preventing lipid peroxidation-induced cell death.
System xCT (Cystine/Glutamate Antiporter): System xCT, the important determinant of intracellular synthesis of glutathione, mediates the exchange of extracellular cystine for intracellular glutamate, thereby regulating intracellular redox balance. Inhibition of xCT leads to depletion of intracellular cysteine, a precursor for GSH synthesis, compromising cellular antioxidant defenses and sensitizing cells to ferroptosis.
Nuclear Factor Erythroid 2–Related Factor 2 (Nrf2): Nrf2 is considered a master regulator of the expression of the genes related to ferroptosis, including GPX4 and xCT. In addition, Nrf2 has been shown to maintain iron homeostasis by regulating the synthesis and degradation of ferritin.
