Mapping safety in space: the emerging role of spatial transcriptomics in safe drug development

Bulk tissue transcriptional profiling has played a key role in drug discovery and preclinical safety assessment by revealing mechanisms of toxicity. However, analyzing gene expression from whole tissues is challenging when toxicities are restricted to specific cell types or regions. Newer sequencing methods, including single-cell RNA sequencing and spatial transcriptomics, enable researchers to study cellular and spatial responses at higher resolution. These techniques provide unique insights into localized gene expression changes linked to drug toxicity. Despite their promise, spatial methods are not always the most practical option, as they present challenges related to cost, data complexity, and the need for specialized analytical expertise. Selection of an appropriate platform may depend on study objectives, tissue and species context, and the distribution of affected regions. Thoroughly assessing each platform's analytical strengths, resolution, and practical limitations is crucial for effectively applying spatial transcriptomics in preclinical safety research. In this review, we evaluate spatial transcriptomic approaches to inform omics platform selection for preclinical safety studies, highlighting platform-specific strengths and considerations specific to drug development.