Multi‐Target Cardioprotective Potential of Garcinia indica Choisy in Olanzapine‐Induced Cardiometabolic Dysregulation: Evidence From Computational and Experimental Insights in H9c2(2‐1) Cells

Olanzapine (OLZ), a commonly prescribed atypical antipsychotic, is strongly linked to cardiometabolic disorders (CMDs) such as obesity, insulin resistance, dyslipidemia, and cardiac dysfunction. Garcinia indica Choisy (kokum), a nutrient-rich medicinal fruit with antioxidant, anti-obesity, antidiabetic, and cardioprotective properties, has not yet been investigated for its potential to counter OLZ-induced CMD(s). This study examined the protective effects and underlying mechanisms of G. indica hydroalcoholic extract (GIE) against OLZ-induced cardiometabolic alterations using in vitro and computational approaches. GIE significantly reduced OLZ-induced cytotoxicity in H9c2(2-1) cardiomyocytes by lowering lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and nitric oxide (NO) levels, while enhancing glucose utilization. Gene expression analysis showed downregulation of IL6, BAX, CASP3, and CAMK2B, alongside upregulation of BCL2, indicating anti-inflammatory and anti-apoptotic modulation. Network pharmacology and in silico analyses identified thirteen phytocompounds targeting 35 CMD-related proteins, with gambogic acid- RAGE and amentoflavone- CALM1 interactions demonstrating the strongest binding affinities, supported by docking and molecular dynamics simulations. Overall, GIE exhibits multi-target regulatory effects on oxidative, inflammatory, and metabolic pathways, suggesting its therapeutic potential in mitigating OLZ-induced cardiometabolic disturbances. The current findings indicate promising mechanistic potential of GIE against OLZ- induced cardiometabolic alterations, warranting further validation through in vivo and clinical studies.