Repurposing troglitazone and pioglitazone as breast cancer therapeutics: An integrated computational study

Breast cancer remains a leading cause of cancer-related mortality among women, creating an urgent need for new therapeutic strategies. This study evaluates the repurposing potential of the anti-diabetic agents Pioglitazone and Troglitazone as breast-cancer therapeutics through an integrated computational workflow encompassing network pharmacology, gene-expression correlation, molecular docking, molecular dynamics (MD) simulations, and pathway enrichment. Network pharmacology analysis highlighted key targets (PPARG, EGFR, HPGD, KDR) enriched in EGFR tyrosine-kinase inhibitor–resistance and focal-adhesion pathways. Epigenetic assessment revealed promoter hypermethylation of PPARG and EGFR correlated with reduced expression (EGFR: r = –0.43; PPARG: r = –0.21), indicating potential transcriptional silencing. Molecular docking demonstrated Troglitazone’s consistently stronger binding, with a highest affinity of –10.6 kcal/mol against HPGD, compared to Pioglitazone’s best score of –9.9 kcal/mol. Both the drugs outperform the reference drug Tamoxifen. MD simulations and post-MD MM/GBSA analysis confirmed that the Troglitazone–PPARG complex maintained stable conformations with a favorable binding free energy (ΔG ≈ –22 kcal/mol), supporting robust ligand–protein interactions. These findings nominate Troglitazone as a structural lead for HPGD–modulating agents aimed at overcoming resistance and enhancing apoptosis in breast cancer. As an entirely in-silico investigation, the results require experimental validation in cellular and animal models before clinical application, and Troglitazone’s known risk of severe hepatotoxicity restricts its direct clinical use, positioning it instead as a structural template for safer analogs.