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.

Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due to the presence of mitochondrial uncoupling protein 1 (UCP1). The appearance of thermogenically active beige adipocytes in iWAT is known as browning. Both brown and beige cells originate from mesenchymal stem cells (MSCs), and in culture conditions a browning response can be induced with hypothermia (i.e. 32 °C) during which nuclear leptin immunodetection was observed. The central role of leptin in regulating food intake and energy consumption is well recognised, but its importance in the browning process at the cellular level is unclear. Here, immunocytochemical analysis of MSC-derived adipocytes established nuclear localization of both leptin and leptin receptor suggesting an involvement of the leptin pathway in the browning response. In order to elucidate whether leptin modulates the expression of brown and beige adipocyte markers, BAT and iWAT samples from leptin-deficient (ob/ob) mice were analysed and exhibited reduced brown/beige marker expression compared to wild-type controls. When MSCs were isolated and differentiated into adipocytes, leptin deficiency was observed to induce a white phenotype, especially when incubated at 32 °C. These adaptations were accompanied with morphological signs of impaired adipogenic differentiation. Overall, our results indicate that leptin supports adipocyte browning and suggest a potential role for leptin in adipogenesis and browning.

Several studies report the important role of an altered gut microbiota in the development of obesity, highlighting the potential use of probiotics in the treatment of obesity. The aim of this study is to investigate the effect of a novel probiotic approach on the expression of specific miRNAs and mRNAs associated with obesity in combination with the hypocholesterolemic octacosanol. Twenty overweight/obese women participated in a randomized, placebo-controlled, double-blind study and were randomly divided into two groups: the intervention group (daily one capsule containing Lactobacillus plantarum 299v (DSM9843), Saccharomyces cerevisiae var. boulardii, and 40 mg octacosanol; N = 12) and the placebo group (N = 8). Changes in lipid parameters and expression of miRNAs and mRNAs were assessed before (T0) and after the 12-week intervention (T1). After the intervention, the expression of miR-155-5p (9.38 ± 0.85 vs. 8.38 ± 1.06, p = 0.05) and miR-24-3p (3.42 ± 0.38 vs. 2.71 ± 0.97, p = 0.031) showed significant decreases in the intervention group when compared to the control group. At T1, the expression of miR-155-5p (8.69 ± 1.31 vs. 9.3 ± 0.85, p = 0.04), miR-125b-5p (5.41 ± 1.18 vs. 5.99 ± 1.36, p = 0.049), and TNF-α (10.24 ± 1.66 vs. 11.36 ± 1.12, p = 0.009) were significantly decreased in the intervention group. No changes in lipids and anthropometric parameters were observed. The novel probiotic approach had a positive effect on regulating the expression of certain miRNAs and mRNAs important for regulating inflammation and adipogenesis, which are essential for obesity onset and control.

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.