Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from −5.5 kcal/mol to −6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from −7.5 kcal/mol to −9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = −9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Withaferin A (WA), a bioactive steroidal lactone derived from Withania somnifera, has been reported to exhibit diverse pharmacological activities, including anti-inflammatory and metabolic regulatory effects. Although previous studies suggest a potential link between WA and thyroid-related molecular pathways, the molecular mechanisms underlying these effects remain incompletely understood. Here, we employed a comprehensive computational approach to explore WA-responsive molecular changes potentially relevant to thyroid-associated processes. RNA-sequencing data from WA-treated MCF-10A human mammary epithelial cells (GSE158085) were analysed to identify differentially expressed genes (DEGs). Because thyroid-specific WA transcriptomic datasets are not currently available, the DEGs were intersected with curated hypothyroidism-associated genes to generate a cross-tissue, exploratory set of candidate genes. The genes that overlapped were used to construct protein–protein interaction networks, prioritize high-centrality candidate genes, and conduct enrichment analyses for transcription factors and kinases. Further analysis of selected upstream kinases was performed using molecular docking and molecular dynamics simulations with WA. A total of 1458 differentially expressed genes (DEGs) were identified, 10 of which overlapped with hypothyroidism-associated genes. Network analysis identified candidate interactions among the overlapping genes, while higher-confidence analysis retained four connected genes (PTPN22, STAT4, DUOX2, and DUOXA2). Transcription factor enrichment identified ERG, SUZ12, NANOG, TCF3, RUNX1, and TP63 as potential upstream regulators, while kinase enrichment identified candidate upstream kinases associated with the predicted regulatory network. Based on enrichment evidence, structural availability, and literature-supported biological relevance, MAPK14 (p38α), AKT1, and MAPK8 (JNK1) were selected for molecular docking and molecular dynamics simulations. Structural analyses suggested potential interactions between WA and the selected kinases, with target-specific dynamic behaviour across the simulated systems. Collectively, the findings highlight WA-responsive genes and predicted gene–TF–kinase relationships that may be relevant to thyroid-associated molecular processes. However, these associations are hypothesis-generating and provide a basis for further investigation in thyroid-derived experimental models.