SGLT2 inhibitor dapagliflozin attenuates pro-oxidative cardiomyocyte injury induced by PI3K selective inhibitor alpelisib and fulvestrant under hyperglycemia

Background Targeting the PI3Kα pathway with alpelisib in combination with endocrine therapy has reshaped the management of PIK3CA-mutant HR+/HER2− breast cancer, as established in the SOLAR-1 trial. Nonetheless, PI3Kα inhibition is frequently complicated by severe hyperglycaemia, a recognised driver of cardiovascular dysfunction and a hallmark risk factor in cardio-oncology. Beyond systemic metabolic derangements, the direct impact of PI3Kα-targeted therapy on cardiomyocyte integrity in hyperglycaemic conditions remains poorly characterised. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as potent cardioprotective agents across diverse cardiometabolic phenotypes, prompting investigation into their role in oncology-related cardiotoxicity. Methods Human induced pluripotent stem cell–derived cardiomyocytes were exposed to the PI3Kα-selective inhibitor alpelisib in combination with the estrogen receptor degrader fulvestrant under sustained hyperglycaemic stress (50 mM glucose), modelling the metabolic milieu observed in treated breast cancer patients. The SGLT2 inhibitor dapagliflozin was administered concomitantly. Cardiomyocyte viability, mitochondrial membrane potential, oxidative stress, and apoptotic signalling (BNP, cardiac troponin I, caspase-3 activation) were quantitatively assessed. Bulk RNA sequencing was performed to interrogate cardiometabolic and inflammatory transcriptional programs. Results Combined PI3Kα and endocrine blockade under hyperglycaemic conditions induced marked mitochondrial dysfunction, excessive reactive oxygen species generation, and activation of pro-apoptotic pathways in human cardiomyocytes. Dapagliflozin co-treatment significantly preserved mitochondrial bioenergetics, attenuated oxidative stress, and suppressed apoptosis-related biomarkers. Transcriptomic profiling revealed downregulation of insulin-stress, inflammatory, and maladaptive metabolic signalling pathways, consistent with restoration of cardiometabolic homeostasis. Conclusions These findings identify a previously underappreciated cardiotoxic liability of PI3Kα-targeted therapy in hyperglycaemic states and demonstrate that SGLT2 inhibition exerts direct cardioprotective effects at the cellular level. The data provide a mechanistic rationale for integrating SGLT2 inhibitors into cardio-oncology strategies aimed at reducing cardiovascular risk and enhancing therapeutic tolerability in patients with PIK3CA-mutant breast cancer.