Forskolin as a multi-target modulator of the oncogenic PI3K/Akt signaling pathway: An in silico integrative GO/KEGG enrichment analysis and network pharmacology

Abstract

Forskolin (FSK), a natural diterpene plant metabolite, exhibits promising anticancer properties, yet its molecular mechanisms remain to be fully elucidated. The current study employs an in silico integrative framework to systematically evaluate FSK anticancer mechanistic potential, paving its repurposing from a traditional natural remedy to a validated, multitargeted oncological therapy. Database mining was used to predict cancer and FSK-related protein targets. Then, the intersect FSK/Cancer common core targets [n=89] were identified. A protein-protein interaction (PPI) network was constructed to identify the gene hubs of core targets. Functional enriched GO/KEGG annotation and cluster analysis were performed to predict molecular pathways and metabolic modules involved in FSK anti-cancer effect. Our results reveal that FSK predominantly targets the PI3K/Akt signaling pathway and its associated oncogenic network. Significant enrichment in PI3K/Akt, EGFR, and Ras pathways, alongside key metabolic modules, underscores FSK potential to inhibit proliferation, induce apoptosis, and alter cancer metabolism. Among the 14 hub genes identified, AKT1, EGFR, PIK3CA, and TP53 further highlight FSK multi-targeted mechanism. These findings provide a molecular framework for the continued development of FSK as a targeted anticancer therapy.