Loganic acid ameliorates diabetic cardiomyopathy via suppressing TLR4/p38 MAPK signaling-mediated oxidative stress and inflammation.

Diabetic cardiomyopathy (DCM), a life-threatening cardiovascular complication of diabetes, manifested as progressive cardiac dysfunction mediated through oxidative stress, inflammation, and apoptosis. Loganic acid (LA), a natural iridoid compound with anti-inflammatory and antioxidant properties, has demonstrated therapeutic potential in various inflammatory disorders, but its role in DCM remains unexplored. Here, we systematically investigated LA's cardioprotective potential and its mechanisms. Utilizing a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model, LA (30 ‍mg/kg, oral gavage) was administered for 8 weeks post-diabetes confirmation. Echocardiographic assay indicated that LA improved cardiac function. Histopathologic evaluation displayed that LA attenuated myocardial structural disorders, reduced collagen deposition, and suppressed cardiomyocyte apoptosis. Furthermore, LA treatment normalized redox imbalance (decreased MDA and increased GSH) and reduced inflammatory cytokine levels. In vitro, a diabetic cell model was established with AC16 cardiomyocytes exposed to high glucose (HG; 30 ‍mM). The findings demonstrated that LA (25 or 50 ‍μM) dose-dependently ameliorated HG-induced cardiomyocyte damage, oxidative stress, and inflammatory cytokine release. Mechanistically, LA treatment suppressed HG-induced activation of TLR4 signaling and phosphorylation of p38 MAPK. Collectively, these findings highlight LA as a novel therapeutic candidate in DCM, targeting the TLR4/p38 MAPK axis to attenuate diabetes-induced cardiac damage.