Confronting the known unknown: historical lessons and future strategies for Disease X.

The 2026 outbreak of Nipah virus in West Bengal, India, a known WHO priority pathogen, serves as a timely reminder of the constant threat from high-consequence emerging diseases and underscores the critical relevance of Disease X-a future pandemic caused by an unknown pathogen. The profound global health and economic impact of COVID-19 has made the potential devastation of Disease X tangible. However, despite the insights gained from COVID-19, significant gaps remain in translating this awareness into an effective, coordinated, and pre-emptive preparedness strategy. This review advances an integrated response framework built around a One Health surveillance diagnostic therapeutic continuum. This foundational system enables real-time pathogen tracking and host immune profiling across human, animal, and environmental interfaces. Insights generated through this continuum directly inform the timely activation of non-pharmaceutical interventions, guide dynamic modeling, and enable the precise deployment of rapid medical countermeasures. Furthermore, these measures should be supported by resilient health infrastructure and equitable data sharing mechanisms, and be embedded within a governance model that prioritizes global collaboration and equity. Ultimately, mitigating Disease X requires a unified strategy that seamlessly integrates continuous monitoring, diagnostics, and treatment within a resilient and equitable operational architecture, thereby transforming pandemic preparedness from concept into reality.