Why the study?
Diabetes mellitus and cancer often coexist, increasing liver injury risk, and while dapagliflozin and trimetazidine have reported hepatoprotective actions against doxorubicin hepatotoxicity, their combined effects remain unclear.
Does dapagliflozin and/or trimetazidine reduce liver injury in a diabetic rat model with doxorubicin-induced hepatotoxicity?
Does dapagliflozin and/or trimetazidine reduce liver injury in a diabetic rat model with doxorubicin-induced hepatotoxicity?
In a rat model of diabetes and doxorubicin-induced liver injury, dapagliflozin and trimetazidine provided hepatoprotective effects through distinct mechanisms, with additive benefits when combined.
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.
No takes yet. Share an insight, caveat, or question.
Çiftel et al. (2025) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: