When Side Effects Become Therapies: A Mechanistic Taxonomy of Adverse Drug Reactions as Translational Signals for Drug Repositioning

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Abstract
Background: The systematic conversion of adverse drug reactions (ADRs) into new therapeutic indications represents one of the oldest and most productive sources of repositioned drugs; however, it has not been subjected to formal mechanistic analysis. Objectives: This study aims to propose a mechanistic taxonomy of convertible ADRs and a structured workflow for translating documented adverse effects into testable repositioning hypotheses. Methods: In this narrative review, historical cases of ADR‐driven repositioning spanning five decades—from sildenafil and minoxidil to semaglutide—were analyzed and classified within a four‐dimensional framework organized along the axes of: (1) target identity (on‐target versus off‐target conversion); (2) dose, route of administration, and reformulation; (3) patient population and clinical context; and (4) pharmacogenomic variability. Results: Each historical case was successfully classified within the proposed taxonomy. A five‐step theoretical workflow—comprising signal identification, taxonomic classification, mechanistic verification, feasibility assessment, and preliminary evidence search—was developed to operationalize the framework for prospective hypothesis generation. Computational tools including side‐effect similarity networks, network pharmacology, and transcriptomic signature reversal were identified as means to support specific workflow steps. Conclusions: The proposed taxonomy and workflow provide a replicable, mechanism‐informed approach to ADR‐driven drug repositioning, while also delineating the pharmacological, regulatory, and methodological challenges that separate a repositioning signal from an approved therapeutic indication.

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