Empagliflozin Attenuates Cardiac Fibrosis via Suppression of TLR2/NF-κB Signaling in a Rat Model of Metabolic Syndrome

The global prevalence of metabolic syndrome (MetS) is rising at an alarming rate. A critical complication of MetS is cardiac fibrosis eventually leading to cardiac dysfunction and death. Therefore, mitigating cardiac fibrosis is essential. Although empagliflozin (EMP) has demonstrated potent cardioprotective and antihyperglycemic properties, it is not yet the primary treatment for MetS. This highlights a critical need to explore EMP’s molecular benefits in MetS populations. This study investigated whether empagliflozin (EMP) attenuates cardiac fibrosis through suppression of TLR2/NF-κB signaling in a rat model of metabolic syndrome (MetS). Sprague–Dawley rats were assigned to a normal diet group and to a high-fat, high-sucrose (HFHS) diet followed by streptozotocin injection to induce MetS. MetS animals were further divided into untreated MetS, MetS treated with EMP 1 mg/kgBW, and MetS treated with EMP 30 mg/kgBW for nine weeks. Cardiac histopathology was evaluated using Hematoxylin–Eosin and Masson’s Trichrome staining, with fibrosis quantified as collagen volume fraction (CVF). mRNA expression of TLR2 and NF-κB was assessed by RT-PCR. Immunofluorescence was performed to evaluate α-SMA expression and nuclear translocation of the NF-κB p65 subunit, a functional indicator of pathway activation. EMP treatment improved metabolic parameters, including fasting blood glucose, triglyceride, and high-density lipoprotein levels. MetS significantly increased TLR2 and NF-κB expression, enhanced nuclear localization of NF-κB p65, elevated α-SMA expression, and promoted interstitial collagen deposition. EMP treatment attenuated these changes, as demonstrated by reduced CVF, downregulation of TLR2 and NF-κB mRNA expression (P < 0.05), diminished p65 nuclear translocation, and decreased α-SMA expression (P < 0.05). Casp1 expression was not significantly altered. In conclusion, empagliflozin attenuates cardiac fibrotic remodeling in a rat model of metabolic syndrome via suppression of TLR2/NF-κB signaling, as supported by reduced p65 nuclear translocation and decreased myofibroblast activation.