Metabolic Modulation by Sglt2 Inhibitors Canagliflozin and Dapagliflozin: A Novel Strategy to Balance Antitumor Efficacy and Cardiotoxicity in Her2–positive Breast Cancer Therapy

Background The clinical use of doxorubicin and trastuzumab in HER2–positive breast cancer is limited by significant cardiotoxicity. Sodium–glucose cotransporter 2 inhibitors (SGLT2is), such as canagliflozin and dapagliflozin, have demonstrated cardiovascular protection in diabetes and heart failure, and emerging evidence suggests potential antineoplastic activity. Whether SGLT2is can simultaneously enhance antitumor efficacy and protect cardiomyocytes during chemotherapy remains unclear. Methods Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC–CMs) and HER2–positive breast cancer cell lines (BT–474, SKBR3) were co–exposed to doxorubicin (1 µM) and trastuzumab (10 µg/mL), alone or in combination with canagliflozin (10 µM) or dapagliflozin (5 µM). Cell viability and apoptosis were quantified via MTT assay, Annexin V/PI staining, and caspase–3/7 activity. Oxidative stress (ROS production, mitochondrial membrane potential), inflammatory markers (IL–1β, TNF–α, NF–κB signaling), and stress–response proteins (NLRP3, MyD88, CXCR4) were evaluated by ELISA, Western blot, and immunofluorescence. Pathway analysis included AMPK activation, SIRT1, and Nrf2 signaling in cardiomyocytes, and GLUT1/GLUT3 modulation in tumor cells. Results Both canagliflozin and dapagliflozin significantly enhanced the cytotoxicity of doxorubicin–trastuzumab in HER2–positive breast cancer cells, as evidenced by reduced proliferation and increased apoptotic activity (p ‹ 0.001). In contrast, in hiPSC–CMs exposed to chemotherapy, both agents preserved cell viability, reduced ROS generation, and maintained mitochondrial potential. Inflammatory cytokine release (IL–1β, TNF–α) and NLRP3 inflammasome activation were markedly attenuated by SGLT2is. Mechanistically, cardioprotection was associated with upregulation of AMPK–SIRT1–Nrf2 pathways, while the enhanced antitumor effect correlated with downregulation of glucose transporters and metabolic stress induction in HER2+ cells. Notably, canagliflozin exerted stronger antitumor synergy, whereas dapagliflozin displayed more pronounced cardioprotective effects. Conclusion This study demonstrates a dual effect of SGLT2 inhibitors in vitro: potentiation of chemotherapy–induced cytotoxicity in HER2–positive breast cancer cells and attenuation of cardiotoxicity in human cardiomyocytes. These findings suggest that SGLT2 inhibition may represent a novel therapeutic approach in cardio–oncology.