TFF3 Gene as a Molecular Target Potentially Shared by Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension: Drug Repurposing Prospect with Aminoglutethimide

Abstract

Idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH) are two chronic conditions that can coexist occasionally, resulting in high morbidity and mortality. Despite their clinical association, the underlying genetic mechanisms and therapeutic targets that might link these two chronic disorders remain poorly understood. The present study used in silico analyses and machine learning to uncover genetic features and potential therapeutic targets shared by IPF and PH. Differentially expressed genes (DEGs) were identified using RNA sequencing data from the Gene Expression Omnibus, which revealed a total of 13 common DEGs between IPF and PH. Importantly, among the identified genes, TFF3 was significantly upregulated in both diseases. TFF3 is targeted by aminoglutethimide as identified through the Drug Gene Interaction Database, and with an interaction score of 3.26. Using the Protein Contact Atlas, PROCHECK, PROSA, and ProtParam tools, the structural model of TFF3 was validated. Finally, molecular docking analysis demonstrated a binding affinity score of −6.1 kcal/mol between TFF3 and aminoglutethimide, indicating a stable and potentially effective interaction between aminoglutethimide and the target protein. Aminoglutethimide displayed favorable ADMET properties as well. In conclusion, this in silico study reports (1) potential overlapping molecular links between IPF and PH, and (2) in silico potential of aminoglutethimide and TFF3 in drug repurposing for therapeutic interventions targeting both IPF and PH. These findings also challenge the traditional paradigm of pharmaceutical innovation that has long relied on the “one drug, one disease” premise, and highlight the potentials of “one drug, polydisease” paradigm of drug discovery and development.