Romanian Society of Pharmaceutical Sciences
 

« Back to Farmacia Journal 6/2025

EXPLORING NOVEL PATHWAYS MODULATED BY PIOGLITAZONE THROUGH NETWORK PHARMACOLOGY AND GENE EXPRESSION ANALYSIS

DALILA BALDERAS-RENTERIA 1, BRYAN ALEJANDRO ESPINOSA-RODRIGUEZ 2, KARLA RAMIREZ-ESTRADA 2, NANCY ELENA GUZMAN-DELGADO 4, XRISTO ZARATE 3 , KATIUSHKA AREVALO-NIÑO 1, ISAIAS BALDERAS-RENTERIA 2*

1 Universidad Autonoma de Nuevo Leon, Facultad de Ciencias Biologicas, Instituto de Biotecnologia, San Nicolas de los Garza, Nuevo Leon, 66455, Mexico
2 Universidad Autonoma de Nuevo Leon, Facultad de Ciencias Quimicas, Laboratory of Molecular Pharmacology and Biological Models, Monterrey, Nuevo Leon, 64570, Mexico
3 Universidad Autonoma de Nuevo Leon, Facultad de Ciencias Quimicas, Laboratory of Protein Expression and Purification, Monterrey, Nuevo Leon, 64570, Mexico
4 Health Research Division, High Specialty Medical Unit, Cardiology Hospital N. 34. Mexican Social Security Institute, Monterrey 64360, Mexico

Download Full Article PDF

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised by chronic hyperglycaemia and insulin resistance (IR), leading to severe complications. Pioglitazone, a PPARγ agonist, improves glycaemic control but is limited by adverse effects, such as weight gain, oedema and risk of fractures. This study aimed to investigate the molecular actions of pioglitazone to identify novel therapeutic targets for safer and more selective treatments. Using network pharmacology, 100 targets were predicted for pioglitazone, including PPARγ, mTOR and GSK-3β. Comparative analyses identified 49 and 90 overlapping targets with T2DM and IR, respectively. Enrichment analyses highlighted key pathways, including PI3K-Akt, FoxO and AGE-RAGE signalling, as well as carbohydrate metabolism and endoplasmic reticulum (ER) stress. Experimental validation in a diabetic murine model confirmed these findings, revealing significant transcriptomic modulation in the liver. Pioglitazone upregulated genes were involved in glucose homeostasis and cellular stress responses, while downregulated genes were involved in oxidative stress and inflammation pathways. Notably, pioglitazone exerted broader effects than recombinant PPARγ, suggesting PPARγ-independent actions. Novel targets, such as ketohexokinase and ER stress components, were identified as promising candidates for future therapies. This integrative approach highlights the potential of combining computational and experimental strategies for drug discovery in T2DM.