Drug Repurposing in Experimental Pharmacology: From Mechanism to Translational Proof

Prohibitive costs and high attrition rates frequently hinder traditional drug discovery. Drug repurposing provides a strategic and cost-efficient approach to addressing urgent unmet medical needs by leveraging existing, clinically approved compounds for new therapeutic indications. However, to move the field beyond serendipitous discovery toward a rigorous, evidence-based paradigm, we must bridge the gap between initial pharmacological observations and clinical reality. This Research Topic spotlights the mechanistic-to-translational workflows that reveal how "old" molecules gain "new" life. We seek high-quality research that emphasizes molecular deconvolution, target engagement, and robust experimental validation to justify the transition from bench to bedside.The scope of this Research Topic encompasses:❖ The entire repurposing pipeline, beginning with advanced discovery methodologies such as AI-guided inference, network pharmacology, and multi-omics integration to identify novel drug-target interactions. ❖ Contributions that provide deep mechanistic insights into the identified ‘HIT,‘ including mapping pathway rewiring using state-of-the-art tools like chemoproteomics and CRISPR perturbations, and uncovering unanticipated polypharmacology that drives either efficacy or toxicity. ❖ Studies that utilize quantitative pharmacology and systems modelling to link drug exposure and target occupancy directly to phenotypic outcomes across diverse genetic backgrounds and disease states.❖ Studies that utilize physiologically relevant models—such as patient-derived organoids, CRISPR-edited systems, or complex organismal models—to provide the necessary "proof of concept" for human trials. ❖ Contributions that offer a clear dose rationale based on PK/PD concordance. ❖ Methodological advances, such as causal inference frameworks and cross-species translation tools, as well as "negative results" that critically refine existing hypotheses. ❖ Studies that establish best practices for de-risking repurposing candidates by connecting molecular mechanisms to clinically meaningful effects and discussing practical hurdles—including regulatory pathways like the FDA’s 505(b)(2) and biomarker discovery for patient stratification.To ensure the highest standards of pharmacological rigour, all manuscripts must comply with The Four Pillars of Ethnopharmacology. You can freely download the full version here. Submissions involving plant extracts or natural preparations must meet these minimum standards for sample characterization. Furthermore, authors are required to evaluate their manuscripts using the ConPhyMP tool to ensure compliance with the standards outlined in the ConPhyMP statement (Front. Pharmacol. 13:953205). Through this intersection of mechanistic clarity and functional validation, we aim to accelerate equitable access to effective, sustainable therapies across the global healthcare system.Please note that submissions lacking experimental validation of in silico findings will not be considered. Topic editors: Dize Darline, Dr. Varun Gorki, SARASWATI PATEL, Francine TANKEU NZUFO, Laychiluh Bantie Mekonnen, Jimma Lenjisa Source: https://www.frontiersin.org/research-topics/76539/drug-repurposing-in-experimental-pharmacology-from-mechanism-to-translational-proof