<p>Metabolic syndrome (MetS) and Type-2 diabetes mellitus (T2DM), often termed “glucolipotoxicity” or insulin resistance syndrome, are complex metabolic disorders typically managed by lifestyle interventions and oral hypoglycemic agents. While conventional drugs, including metformin, sulfonylureas, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, show efficacy, they also present risks such as hypoglycemia and weight gain. Among these, metformin remains the preferred first-line treatment due to its safety, low cost, and minimal side effects. However, the multifactorial nature of MetS/T2DM, coupled with increased cardiovascular risk, demands novel therapeutic strategies targeting broader disease-specific mediators. This study employs network pharmacology to identify potential gene targets linked to MetS/T2DM. We constructed a protein-protein interaction (PPI) network of 97 genes involved in the pathophysiology of these disorders, identifying 89 interlinked genes. The top 10 crucial genes including insulin receptor substrate 1 (IRS1), and interleukin-6 (IL6) are highlighted as key contributors to disease progression. Gene Ontology (GO) analysis revealed their involvement in essential biological processes like peptide synthesis, lipid regulation, and glucose homeostasis. Interestingly, nine of these genes are influenced by metformin, suggesting its broader mechanism in modulating metabolic pathways. Additionally, scrutiny of transcription factors for the considered dataset shows that forkhead box protein O1 (FOXO1), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) play crucial roles in insulin signalling, mitochondrial function, and glucose metabolism, further elucidating the molecular complexity of T2DM. Through a network biology framework, this study attempts to highlight the potential for prospective multi-targeting therapeutic strategies that may exhibit improved efficacy and safety, for the management of MetS/T2DM.</p>