Synergizing In Vitro and energy-based computational approaches to investigate the potential of Lagenaria siceraria against olanzapine-induced cardiometabolic disorders using H9c2 (2-1) cardiomyocytes

• Evaluated the cardioprotective effect of L. siceraria on Olanzapine treated H9c2 (2-1) cells. • LSE showed reduction in LDH, CK-MB, NO and, glucose utilization assay. • LSE downregulated IL6, BAX, CASP3, CAMK2B, and upregulated BCL2 expression by qRT-PCR Olanzapine (OLZ), a widely prescribed atypical antipsychotic, is notably associated with the onset of cardiometabolic disorders (CMDs). Lagenaria siceraria, traditionally recognized for its cardioprotective effects and benefits for CMD(s). However, its potential in mitigating OLZ-induced CMD(s) has not been extensively explored. This study aims to assess the efficacy and underlying mechanisms of Lagenaria siceraria hydroalcoholic extract (LSE) in counteracting OLZ-induced CMD(s) through in vitro and computational approaches. The effects of LSE on OLZ-challenged H9c2 (2-1) cardiomyoblasts were evaluated by measuring lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), nitric oxide (NO), and glucose utilization. Additionally, the expression of essential key genes (such as IL6, BAX, BCL2, CASP3, CAMK2B) implicated in OLZ-induced CMD(s) was analysed using qRT-PCR. Computational analyses, including gene set enrichment, network pharmacology, and molecular docking via (AutoDock Vina, POAP pipeline), followed by molecular dynamics (MD) simulations, MM-PBSA, and binding stability assessments via (GROMACS), were employed to predict compound-target interactions. The results demonstrated that LSE significantly attenuated OLZ-induced elevations in LDH, CK-MB, and NO levels while enhancing glucose utilization in cardiomyoblasts. LSE also modulated gene expression by downregulating IL6, BAX, CASP3, and CAMK2B, while upregulating BCL2. Network pharmacology identified 10 phytocompounds from LSE targeting 17 common proteins involved in OLZ-induced CMD(s), with beta-sitosterol- AKT and beta-sitosterol- CALM1 complexes exhibiting the strongest binding affinities. MD simulations confirmed the stability of these interactions over a 100 ns period. In conclusion, the findings suggest that LSE holds cardioprotective potential against OLZ-induced CMD(s). Further research, including studies with purified compounds and clinical trials, is necessary to evaluate LSE as an adjunctive therapeutic agent.