Avian influenza H5N1: A warning signal for the next influenza pandemic.

Highly pathogenic avian influenza A (H5N1) remains one of the most significant zoonotic threats of the 21st century due to its wide host range, high case-fatality rates in humans, and ability to cause devastating losses in poultry and wildlife. Since its first detection in humans in 1997, H5N1 has diversified into multiple genetic clades, with clade 2.3.4.4b now driving a true global panzootic affecting birds, mammals, and livestock across continents. This review synthesizes current knowledge on the virology, genomic evolution, transmission dynamics, and ecological spread of H5N1, with particular emphasis on its recent incursions into dairy cattle, companion animals, and marine mammals. Mechanistic insights into viral proteins, immune dysregulation, and mammalian adaptation highlight the virus's expanding zoonotic potential. Surveillance data demonstrate repeated spillovers at the human-animal-environment interface, although sustained human-to-human transmission has not yet been observed. Preparedness requires a One Health approach that integrates surveillance, early detection, and coordinated responses across veterinary, medical, and environmental sectors. Advances in next-generation vaccines, diagnostics, and therapeutics offer promising countermeasures, but equitable access, ethical oversight of high-risk research, and socio-economic resilience remain critical challenges. Lessons from past pandemics underscore the urgent need for proactive global action to mitigate the pandemic risk posed by H5N1.