The main pathological hallmark of diabetes is the loss of functional β‐cells. Among several types of β‐cell death in diabetes, the involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes‐mimicking factors: high glucose (HG), proinflammatory cytokines, hydrogen peroxide (H₂O₂), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis of β‐cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ‐induced in vivo diabetic model. All in vitro treatments increased loss of Rin‐5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron, inactivation of NF‐E2‐related factor 2 (Nrf2), and decrease in glutathione peroxidase 4 expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer‐1), ferroptosis inhibitor, diminished the above‐stated effects and rescued cells from death in case of HG, STZ, and H₂O₂ treatments, while failed to increase MMP and to attenuate cell death after the cytokines’ treatment. Moreover, Fer‐1 protected pancreatic islets from STZ‐induced injury in diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the population of insulin‐positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of β‐cells, emerging HG, H₂O₂, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for preservation of the β‐cell population. Our results obtained from in vivo study strongly justify this approach.

Cell death plays an important role in diabetes-induced liver dysfunction. Ferroptosis is a newly defined regulated cell death caused by iron-dependent lipid peroxidation. Our previous studies have shown that high glucose and streptozotocin (STZ) cause β-cell death through ferroptosis and that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, improves β-cell viability, islet morphology, and function. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related pathological changes in the liver. For this purpose, male C57BL/6 mice, in which diabetes was induced with STZ (40 mg/kg/5 consecutive days), were treated with Fer-1 (1 mg/kg, from day 1–21 day). It was found that in diabetic mice Fer-1 improved serum levels of ALT and triglycerides and decreased liver fibrosis, hepatocytes size, and binucleation. This improvement was due to the Fer-1-induced attenuation of ferroptotic events in the liver of diabetic mice, such as accumulation of pro-oxidative parameters (iron, lipofuscin, 4-HNE), decrease in expression level/activity of antioxidative defense-related molecules (GPX4, Nrf2, xCT, GSH, GCL, HO-1, SOD), and HMGB1 translocation from nucleus into cytosol. We concluded that ferroptosis contributes to diabetes-related pathological changes in the liver and that the targeting of ferroptosis represents a promising approach in the management of diabetes-induced liver injury.

Recently, we characterized the ferroptotic phenotype in the liver of diabetic mice and revealed nuclear factor (erythroid‐derived‐2)‐related factor 2 (Nrf2) inactivation as an integral part of hepatic injury. Here, we aim to investigate whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes‐induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice were divided into four groups: control (vehicle‐treated), diabetic (streptozotocin‐induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane‐treated (2.5 mg/kg from Days 1 to 42) and non‐diabetic sulforaphane‐treated group (2.5 mg/kg from Days 1 to 42). Results showed that diabetes‐induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic molecules critical for antioxidative defense (catalase, superoxide dismutases, thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferroportin 1), glutathione (GSH) synthesis (cystine‐glutamate antiporter system, cystathionase, glutamate‐cysteine ligase catalitic subunit, glutamate‐cysteine ligase modifier subunit, glutathione synthetase), and GSH recycling ‐ glutathione reductase (GR) were reversed/increased by sulforaphane treatment. In addition, we found that the ferroptotic phenotype in diabetic liver is associated with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the increased level of GSH, decreased accumulation of labile iron and lipid peroxides (4‐hydroxy‐2‐nonenal, lipofuscin), decreased ferritinophagy and liver damage (decreased fibrosis, alanine aminotransferase, and aspartate aminotransferase). Finally, diabetes‐induced increase in serum glucose and triglyceride level was significantly reduced by sulforaphane. Regardless of the fact that this study is limited by the use of one model of experimentally induced diabetes, the results obtained demonstrate for the first time that sulforaphane prevents diabetes‐induced hepatic ferroptosis in vivo through the activation of Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes‐related pathologies.

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, emerged as an important contributor to the pathogenesis of diabetes and its complications. Impaired glucose and iron metabolism, and increased oxidative stress, predispose cells—particularly pancreatic β-cells and vascular tissues—to ferroptotic cell death, contributing to β-cell dysfunction, insulin resistance, and the progression of diabetic complications. Hydrogen sulfide (H₂S), an important gasotransmitter, plays a pivotal role in regulating various pathophysiological processes by interfering with key cellular signaling pathways, including those related to cell death. In the context of ferroptosis, H₂S exerts protective effects by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4/glutathione (Nrf2/GPX4/GSH) axis, enhancing cellular antioxidative defenses and inhibiting lipid peroxidation. Furthermore, H₂S modulates key regulators of iron homeostasis and lipid metabolism, including hepcidin, ferritin, and the cystine/glutamate antiporter system (xCT) antiporter, further attenuating ferroptosis. Exogenous administration of H₂S can reverse ferroptosis-induced cellular injury in several pathological settings and improve metabolic outcomes in diabetic models. These findings suggest that targeting H₂S signaling is a promising therapeutic strategy to inhibit ferroptosis and mitigate diabetes-related organ dysfunction. This review summarizes current insights into the molecular interplay between H₂S and diabetes-related signaling pathways, primarily ferroptosis, emphasizing the antiferroptotic therapeutic potential of H₂S-based interventions for the prevention and treatment of diabetic complications.

Excessive dietary dextrose intake and its misuse in sports raise significant concerns about health outcomes across life stages. To investigate how biological maturity influences small intestinal responsiveness to dextrose overexposure, we subjected 1-month-old (young maturing) and 14-month-old (middle-aged) male Wistar rats to a 20% or 60% dextrose drinking regimen for 8 weeks. The middle-aged rats receiving the 60% dextrose solution exhibited the most pronounced alterations, including compromised barrier integrity, reduced crypt proliferation, and accelerated enterocyte apoptosis and necrosis. These structural changes coincided with weakened antioxidant defences, tissue iron accumulation, and elevated lipid peroxidation. Altered neuroendocrine and purinergic pathways, marked by increased serotonin, neuron-specific enolase (NSE), cytosolic high mobility group box 1 (HMGB1), and ATP synthase, alongside downregulated P2X7 receptor expression and a reduced nuclear factor kappa B p65/nuclear factor erythroid 2-related factor 2 (NF-κB p65/Nrf2) ratio, indicate potential observational associations with metabolic exhaustion and impaired inflammatory responsiveness under a chronic high-dextrose regimen. In conclusion, while fasting homeostatic model assessment of insulin resistance (HOMA-IR) values remained stable, a high-dextrose drinking regimen promotes maturity-dependent small intestinal changes and molecular signalling weakness, providing a preliminary pathophysiological framework for understanding potential health outcomes of dextrose overexposure across different life stages.