Emodin ameliorates diabetic cardiomyopathy by regulating mitochondrial dynamics of fission and fusion and ferroptosis through the AHR‑Nrf2 pathway

Emodin, a natural anthraquinone with known antioxidant properties, has not been fully investigated in diabetic cardiomyopathy (DCM), a condition marked by oxidative stress, ferroptosis and metabolic disturbance, and lacking specific therapies. A DCM model was induced by streptozotocin and a high‑fat diet. Cardiac function after emodin treatment was assessed via echocardiography, while myocardial injury, fibrosis and myocardial iron concentration were evaluated histologically. Mitochondrial fission‑fusion dynamics were examined using transmission electron microscopy and confocal imaging. In vitro functional rescue experiments using Ferrostatin‑1 and aryl hydrocarbon receptor (AHR) knockdown via small interfering RNA or AAV9 was performed to determine its role in emodin‑regulated ferroptosis, lipid peroxidation, mitochondrial dynamics and Nrf2 signaling. Emodin improved left ventricular systolic function, attenuated metabolic disorders, reduced myocardial iron concentration and fibrosis, and suppressed excessive mitochondrial fission and lipid peroxidation in DCM mice. These effects were largely reversed by AHR knockdown. Mechanistically, emodin promoted Nrf2 nuclear translocation and upregulated antioxidant molecules, while AHR silencing abrogated these protective effects, thereby exacerbating ferroptosis and mitochondrial dynamic imbalance. In conclusion, emodin protects against high glucose‑induced cardiac injury and improves mitochondrial function by limiting ferroptosis and restoring mitochondrial fission‑fusion homeostasis, effects that are mediated through the AHR‑Nrf2 pathway. These findings suggest emodin and the AHR‑Nrf2 axis as potential therapeutic targets for DCM.