Reclaiming the Host: Why p53/NRF2-Directed Therapies Should Enter the Global Antiviral Policy Agenda

Respiratory viruses continue to challenge global preparedness because antiviral strategies remain largely pathogen specific. RSV, SARS-CoV-2, influenza, and emerging zoonotic viruses differ genetically, yet increasing evidence suggests that they converge on a common host vulnerability: suppression of the cellular stress-response regulators p53 and NRF2. RSV promotes p53 degradation and NRF2 loss, while SARS-CoV-2 similarly impairs these pathways and amplifies inflammatory signalling. Restoration of p53 and NRF2 reactivates antiviral microRNAs, suppresses viral-entry and inflammatory pathways, restores antioxidant defences, and induces p62/SQSTM1, a broad-spectrum antiviral restriction factor. These observations suggest that host-directed therapies could complement vaccines and direct-acting antivirals by establishing a mutation-resistant layer of protection. We argue that global preparedness frameworks should formally evaluate host-directed antiviral strategies as a third pillar of pandemic readiness.