Diacerein Protects Against Obesity-Related Cardiovascular Injury: Evidence from In Silico and In Vivo Studies.

Obesity constitutes a significant worldwide health challenge and a primary risk factor for cardiovascular diseases. Diacerein, an anti-inflammatory medication approved for osteoarthritis, is being studied as a potential modulator of inflammatory signaling. However, its role in obesity-associated cardiovascular injury remains incompletely understood. In the present study, computational docking and 300-ns MD simulations supported preferential, stable binding of diacerein to the TLR4 complex through a deep, hydrophobic, solvent-shielded pose, consistent with coordinated protein dynamics. Then, the cardioprotective effects of diacerein were examined in a high-fat diet (HFD)-induced obesity model. Male Sprague-Dawley rats were divided into three groups: normal control, HFD, and HFD combined with diacerein (50 mg/kg/day) for 10 weeks. Metabolic parameters, lipid profile, serum troponin I, and C-reactive protein (CRP) were evaluated. A histopathological examination of the heart and aorta was conducted, and the tissue levels of TLR4, MyD88, IRAK1, TRAF6, NF-κB, and downstream pro-inflammatory cytokines (IL-6 and TNF-α) were assessed. Inflammatory cell infiltration was evaluated using CD45 immunohistochemistry. The HFD led to insulin resistance, dyslipidemia, increased troponin I and CRP levels, and significant histological alterations in cardiac and aortic tissues, accompanied by the activation of the TLR4/NF-κB inflammatory pathway and enhanced inflammatory cell infiltration. Diacerein treatment markedly alleviated metabolic abnormalities, diminished cardiac injury and systemic inflammation, improved histological features, and reduced tissue protein levels of the TLR4/NF-κB pathway and pro-inflammatory cytokines. In conclusion, diacerein provides marked protection against obesity-induced cardiovascular injury, at least partially, by inhibiting the TLR4/NF-κB inflammatory pathway, supporting its potential as a therapeutic strategy for obesity-related cardiovascular complications.