SGLT2 Inhibitor Dapagliflozin Attenuates Cardiomyocyte In-jury and Inflammation Induced by PI3Kα-selective inhibitor Alpelisib and Fulvestrant Under Hyperglycemia

Background: Activating PIK3CA mutations occur in approximately 40% of hormone receptor–positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Methods: Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor–induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Results: Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3–mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. Conclusion: This study demonstrates that alpelisib-based therapy under hyperglycemic conditions directly induces oxidative, mitochondrial, and inflammatory injury in human cardiomyocytes, recapitulating key aspects of the cardiometabolic stress observed in patients receiving PI3Kα-targeted therapy. Importantly, dapagliflozin markedly mitigates these effects, suggesting that SGLT2 inhibition may provide direct cardioprotective benefits beyond glycemic control. These findings support the potential repurposing of dapagliflozin as a cardiometabolic protective strategy in patients undergoing PI3Kα inhibitor–based cancer therapy.