Dual-Targeted Mitigation of Diabetic Cardiomyopathy via Phloroglucinol and Procyanidin dimer B1: Suppression of NF-κB-Driven Inflammation and Nrf2-Pathway Activation for Synergistic Cardioprotection in Murine Models

Purpose Diabetic cardiomyopathy (DCM), a major complication of diabetes mellitus, is driven by chronic inflammation and oxidative stress, leading to myocardial remodeling and dysfunction. This study aimed to investigate the synergistic cardioprotective effects of two bioactive compounds—Phloroglucinol (Pg) and Procyanidin dimer B1 (PB1) —by targeting the NF-κB and Nrf2 signaling pathways, and to evaluate their therapeutic potential in both in vitro and in vivo models of DCM. Methods Type 1 diabetes was induced in C57BL/6 mice via streptozotocin (STZ) to establish a murine model of DCM. Parallel in vitro experiments were conducted using H9C2 cardiomyocytes exposed to high glucose (HG) conditions. Pg and PB1, isolated from Vitis vinifera seeds, were administered individually and in combination. Molecular and histological analyses were performed to assess oxidative stress, inflammatory markers (NF-κB activation), antioxidant response (Nrf2 pathway), fibrosis, and cardiac function through echocardiography and biomarker evaluation. Results Treatment with Pg and procyanidin B1 significantly reduced HG-induced oxidative damage and inflammatory cytokine expression in H9C2 cells by inhibiting NF-κB activation and upregulating Nrf2-mediated antioxidant responses. In diabetic mice, combination therapy markedly attenuated cardiac hypertrophy, fibrosis, and left ventricular dysfunction. These effects were corroborated by downregulation of pro-fibrotic and hypertrophic genes and reduced levels of malondialdehyde (MDA) and TNF-α. Improved myocardial architecture and functional recovery were evident in treated groups compared to untreated diabetic controls. Conclusion Pg and PB1 exert synergistic cardioprotective effects against diabetic cardiomyopathy by dually targeting NF-κB-driven inflammation and Nrf2-mediated antioxidant defense. These findings highlight their translational potential as novel adjunct therapeutic agents for mitigating diabetes-induced cardiac damage and improving cardiac outcomes.