Background/Objectives: Diabetic cardiomyopathy is a distinct myocardial dysfunction characterized by structural and functional changes in the heart that occur in diabetic patients independently of coronary artery disease or hypertension. It is closely associated with oxidative stress, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, and contributes to progressive cardiac damage. This study aimed to evaluate the cardioprotective effects of dapagliflozin (DAPA) and trimetazidine (TMZ) in a rat model of doxorubicin-induced cardiomyopathy with streptozotocin-induced diabetes, focusing on their potential mechanisms related to ER stress. Methods: A total of 48 Sprague Dawley rats aged 6–8 weeks were randomly distributed equally into six cages. The diabetes model was induced by intraperitoneal administration of streptozotocin (STZ) and rats with blood glucose levels above 250 mg/dL were considered diabetic. For those rats with diabetes, cardiotoxicity was induced by intraperitoneal injection of 5 mg/kg/week doxorubicin (DOXO) for 4 weeks. After a cumulative dose of 20 mg/kg doxorubicin, a week break was given, followed by the administration of TMZ (10 mg/kg) and/or DAPA (10 mg/kg) to the treatment groups. Results: STZ administration caused diabetes and significant degeneration in cardiomyocytes. With the addition of DOXO (STZ + DOXO), cardiomyocyte degeneration became more severe. When the study groups were histopathologically evaluated based on parameters of degenerative cardiomyocytes, vascular congestion, and edema, it was shown that both TMZ and DAPA, whether applied alone or in combination, reduced damage in heart tissue. Both TMZ and DAPA reduced cardiomyocyte damage, and their combination provided the lowest level of damage through the reduced ER stress pathway by reducing GRP 78 and CHOP positivity. Conclusions: TMZ and DAPA reduce ER stress and have protective effects against diabetic-induced cardiotoxicity. Combination therapy or TMZ was found to be more effective than DAPA in alleviating ER stress. Combination therapy appears to carry potential effects for reducing cardiac cell damage in individuals with diabetes.

Background: Diabetes mellitus and cancer often coexist, increasing the risk of liver injury. Doxorubicin (DOXO) is a widely used antineoplastic drug with known hepatotoxic effects. Dapagliflozin (DAPA) and trimetazidine (TMZ) have been reported to exert hepatoprotective actions, but their combined effects remain unclear. Methods: Forty-eight male Sprague Dawley rats were allocated into six groups: control, streptozotocin (STZ), STZ + DOXO, STZ + DOXO + DAPA, STZ + DOXO + TMZ, and STZ + DOXO + DAPA + TMZ. Liver injury was assessed by histopathology, oxidative stress markers (MDA, GSH), and immunohistochemistry (Tumor Necrosis Factor-alpha (TNF-α), 8-Hydroxy-2′-deoxyguanosine (8-OHdG), Caspase-3, Transforming Growth Factor-beta 1 (TGF-β1), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Nuclear Factor kappa-B/p65 (NF-κB/p65)). Results: STZ and STZ + doxorubicin groups developed marked hepatic injury. Unexpectedly, the STZ + doxorubicin group showed lower alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, along with reduced Malondialdehyde (MDA) and elevated glutathione (GSH), suggesting compensatory antioxidant and apoptotic responses. Dapagliflozin more effectively normalized transaminases and reduced oxidative DNA damage, whereas trimetazidine exerted stronger effects on MDA, GSH, and inflammatory markers. The combination provided additive but not consistently superior benefits. Immunohistochemical analyses confirmed these findings, showing attenuated expression of TNF-α, 8-OHdG, caspase-3, and TGF-β1 and reduced TUNEL-positive hepatocytes and NF-κB/p65 immunoreactivity following treatment, indicating coordinated anti-apoptotic and anti-inflammatory effects. Conclusions: Dapagliflozin and trimetazidine each attenuated diabetes- and doxorubicin-related hepatic injury through partly distinct mechanisms, with the combination providing additive but not consistently superior effects. These findings suggest a potential hepatoprotective role for both agents; however, the clinical implications remain uncertain and require confirmation in further mechanistic and translational studies.