Repurposing antimicrobials, disulfiram, and metformin for cancer therapy: Bridging mechanistic gaps through RNA...

This review focuses on antimicrobials (azithromycin, clarithromycin, clioquinol, chloroquine, doxycycline, erythromycin, ivermectin, and tigecycline), disulfiram, and metformin. It aims to highlight key knowledge gaps and the role of RNA sequencing in the translational repurposing of these agents for cancer therapy. Among the selected repurposed candidates, metformin is distinguished by an abundance of preclinical and clinical studies. Its anticancer activity is partly attributed to the induction of multiple regulated cell death pathways, including apoptosis, pyroptosis, necroptosis, and ferroptosis, alongside transcriptomic changes identified by bulk RNA sequencing across different cancer types. Clinical translation has thus far yielded mixed results, with drug-drug interactions, subtherapeutic concentrations, resistance mechanisms, and components of the tumour microenvironment representing key challenges to be addressed. In future, transcriptomics-guided drug repurposing, which enables patient stratification, together with the strategic use of repurposed agents informed by predictive biomarkers, may improve clinical outcomes. Bulk RNA sequencing provides a cost-effective means to assess drug-induced global gene expression changes, whilst single-cell and spatial transcriptomics offer finer resolution by capturing cell-type-specific responses and stromal influences, thereby enhancing precision in therapeutic targeting.