Opening the black box: insights into ubiquitin-mediated control of innate antiviral immunity and AI-enhanced therapeutics.

Innate antiviral immunity serves as the first line of defence against viral infections by detecting viruses and triggering responses to eliminate infected cells. However, viruses often evade such host defence mechanisms by hijacking essential post-translational modifications (PTMs) involved in these pathways, particularly ubiquitination, which plays a central role in immune signalling and targeted degradation. This makes ubiquitin sites and E3 ligases key targets for developing degradative antiviral therapeutics. Both have been studied extensively for degradative drugs such as Proteolysis Targeting Chimeras (PROTACs), but their antiviral potential still requires further investigation. Parallel advancements in artificial intelligence have transformed drug design, enabling precise de novo design and PTM site predictions, yet AI-based, ubiquitin-centred antiviral strategies remain underexplored. In this review, we connect these areas by examining the role of ubiquitination in antiviral immunity and viral evasion, identifying limitations in current AI-driven approaches, and outlining how AI can be leveraged to design targeted antiviral therapies. We further discuss the need for explainable AI to address interpretability challenges and consider the risks of AI use in healthcare. Finally, we highlight the potential of integrating structural and emerging 4D modelling approaches to better understand dynamic viral protein complexes and support next-generation antiviral design.