Blue-sky vision: Targeting microRNA-21 as a Broad-Spectrum Antiviral Approach

Emerging and re-emerging human viruses pose ongoing global health threats and have been identified by the World Health Organization (WHO) as priority pathogens. The lack of effective therapies for these viruses of pandemic concerns highlights the urgent need for the development of novel broad-spectrum host-directed antiviral strategies. MicroRNAs (miRNA or miR) are small non-coding RNAs that regulate post-transcriptional gene expression by binding to target messenger RNAs (mRNAs), leading to degradation, translational repression, or site-specific cleavage. Viral infections significantly alter host miRNA expression, resulting in either pro- or antiviral effects. Understanding the role of miRNAs in modulating signaling pathways during viral infection is crucial for identifying host-directed strategic targets (HDSTs) for antiviral therapy. This article highlights the potential of targeting miR-21 as a host-directed antiviral approach by discussing the relationship between miR-21 expression and viral infections, and the signaling pathways and cellular hubs that are modulated by miR-21. miR-21 is consistently upregulated in multiple viral infections, including WHO priority pathogens, and is generally associated with increased viral replication and more severe disease outcomes. miR-21 is known to facilitate viral replication and immune evasion in oncolytic virus infections by targeting key host factors such as programmed cell death 4 (PDCD4), phosphatase and tensin homolog (PTEN), and the Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway. These targets contribute to the proviral role of miR-21 by modulating key cellular hubs to accelerate invasion, reduce apoptosis, inhibit autophagy, promote proliferation, and enhance epithelial-mesenchymal transition (EMT), leading to immune evasion. The conserved regulatory functions modulated by miR-21 suggest that it plays a broad role in viral pathogenesis and targeting it could provide a durable antiviral strategy that can address pathogens of global health concern and increase the pandemic preparedness efforts within Canada, and internationally.