Sulfuretin as a Novel Cardioprotective Agent in Type 2 Diabetes: Nrf2-Dependent Protection in a Preclinical Model
Background:
Type 2 diabetes mellitus (T2DM) is frequently complicated by diabetic cardiomyopathy, a major cause of heart failure driven by chronic hyperglycemia, oxidative stress, and inflammation (Kakkar et al., 2025). Despite advances in glycemic control, effective therapies targeting the molecular mechanisms of diabetes-induced cardiac injury remain limited. Sulfuretin, a naturally occurring aurone flavonoid with antioxidant and metabolic regulatory properties, has shown therapeutic potential in metabolic and oxidative stress-related disorders (Li et al., 2025). However, its cardioprotective effects and mechanistic actions in T2DM remain incompletely defined.
Purpose:
This study aimed to evaluate the cardioprotective effects of sulfuretin in experimental diabetic cardiomyopathy in rats with T2DM and to determine the involvement of Keap1/Nrf2 signaling in mediating these effects (Gu et al., 2025).
Methods:
Adult male Wistar rats were assigned to non-diabetic and HFD + streptozotocin-induced diabetic groups (n = 8/group). Each group received vehicle, sulfuretin (5 or 10 mg/kg/day, oral gavage) (Kim et al., 2019), or sulfuretin combined with the Nrf2 inhibitor brusatol (2 mg/kg) (ALTamimi et al., 2023). Cardiac hemodynamics and metabolic indices, as well as cardiac injury markers, lipid peroxidation, antioxidant markers, and several inflammatory mediators, were assessed in the left ventricles of all groups. In addition, cytoplasmic Keap1 and Nrf2, as well as nuclear accumulation of Nrf2, were measured by ELISA, and their expression levels were assessed by qPCR. Finally, hematoxylin and eosin (H&E) staining was performed on left ventricular tissues from all groups to evaluate histopathological changes. Data distribution and homogeneity of variance were evaluated using appropriate normality and variance tests. Intergroup comparisons were performed using one-way or two-way analysis of variance (ANOVA), as appropriate, followed by Tukey’s multiple-comparison test. All experiments were conducted in accordance with the approved ethical protocol.
Results:
In diabetic rats, sulfuretin dose-dependently reduced serum levels of CK-MB, LDH, and troponin I and improved cardiac function by reducing LVEDP and increasing LVSP, +dP/dtmax, and -dP/dtmin. Sulfuretin also markedly reduced malondialdehyde (MDA) levels and enhanced total antioxidant capacity, superoxide dismutase, glutathione, and heme oxygenase-1 expression. In addition, it significantly increased the expression and cytoplasmic and nuclear accumulation of Nrf2 in both control and diabetic left ventricles. Furthermore, sulfuretin suppressed tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels specifically in diabetic left ventricles and preserved cardiomyocyte architecture. Interestingly, sulfuretin failed to alter glucose, lipid, or insulin levels in non-diabetic animals. All of these functional benefits were abolished by brusatol, confirming Nrf2-dependent cardioprotection.
Conclusion:
Sulfuretin confers robust protection against T2DM-mediated diabetic cardiomyopathy through activation of Nrf2-mediated antioxidant and anti-inflammatory pathways, independent of any hypoglycemic or hypolipidemic effects.