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Bridging the validation gap: organoids as functional decision systems in drug repurposing
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DOI：10.1016/j.phrs.2026.108360.png)
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Abstract
En 中文
Drug repurposing offers a faster and less costly route to therapeutic development, yet its translational success remains constrained by a critical scientific and evidentiary gap: the absence of human-relevant intermediate validation systems capable of converting computationally generated candidates into biologically grounded, clinically actionable evidence. In this opinion paper, we propose that human organoid platforms—particularly when integrated with artificial intelligence (AI)-driven candidate prioritisation upstream and multidimensional data analytics downstream—can function as context-specific, fit-for-purpose functional decision layers within repurposing pipelines—decision-grade within a defined context of use rather than as a generalisable property of the platform. We outline a hybrid framework coupling in silico discovery, organoid-based functional validation, and AI-enabled response interpretation, and we propose the disease categories in which this approach is most immediately applicable. We further discuss current operational challenges alongside their enabling solutions, and contextualise the framework within the evolving regulatory landscapes of the FDA and EMA as both agencies advance the integration of New Approach Methodologies (NAMs).
Keywords:
drug repurposing
organoids
in silico
artificial intelligence
new approach methodologies
rare diseases
translational pharmacology
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