Therapeutic potential of the novel anthraquinone compound ESE in T2DM mice by inhibiting of TLR4/MyD88/NF-κB pathway.

BACKGROUND AND

OBJECTIVE

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Although current medications such as metformin can effectively control blood glucose levels, their ability to improve β-cell function and suppress chronic inflammation remains limited. Emodin, a natural compound with anti-inflammatory, antioxidant, and insulin-sensitizing properties, has shown therapeutic promise; however, its clinical application is constrained by poor water solubility and low bioavailability. This study aimed to investigate the therapeutic potential and underlying mechanisms of a novel Emodin Succinyl Ester derivative (ESE) inT2DM.

METHODS

A T2DM mouse model was established using a high-fat diet combined with streptozotocin (STZ) injection. Mice were randomly assigned to four groups: control, T2DM, T2DM + metformin, and T2DM + ESE. ESE was administered via oral gavage at a dose of 40 mg/kg for 6 consecutive weeks. The effects of ESE on blood glucose, lipid profiles, oxidative stress, and inflammatory cytokine levels were evaluated using ELISA, immunohistochemistry, Real-time PCR, Western blot, and transcriptome sequencing. Additionally, the regulatory effects of ESE on the TLR4/MyD88/NF-κB signaling pathway were systematically analyzed.

RESULTS

ESE treatment significantly reduced fasting blood glucose and HbA1c levels in T2DM mice, while improving glucose tolerance and correcting dyslipidemia. Moreover, ESE markedly decreased serum malondialdehyde (MDA) levels and enhanced the activities of antioxidant enzymes, including superoxide dismutase (SOD) and the GSH/GSSG ratio. At the molecular level, ESE suppressed the TLR4/MyD88/NF-κB pathway, resulting in reduced expression of pro-inflammatory cytokines (IL-6 and TNF-α) and increased levels of the anti-inflammatory cytokine IL-10. Histological analyses further revealed that ESE ameliorated the structural and functional deterioration of pancreatic β-cells.

CONCLUSION

ESE improves glucose and lipid metabolism, attenuates oxidative stress and inflammation, and protects pancreatic β-cell function by modulating the TLR4/MyD88/NF-κB signaling pathway in T2DM mice. These findings underscore the significant antidiabetic potential of ESE as a multi-target therapeutic agent, offering a promising new direction for T2DM treatment.