Addressing the zoonotic threat of merbecoviruses.

Merbecovirus is a subgenus of betacoronaviruses and exhibits high genetic diversity with a capacity for cross-species transmission. However, beyond Middle East respiratory syndrome coronavirus (MERS-CoV), our knowledge of the ecology and pathogenic potential of these viruses remains limited. Merbecoviruses were once thought to rely exclusively on dipeptidyl peptidase 4 for cell entry, but recent discoveries have revealed that several members can also engage with angiotensin-converting enzyme 2 or aminopeptidase N, expanding their receptor repertoire and potential host range. Here we summarize recent advances in understanding of the receptor usage of merbecoviruses and examine how these insights inform pandemic preparedness and risk assessment. We discuss the development of targeted diagnostics, broad-spectrum antivirals and vaccines, including pan-coronavirus strategies. Together, these advances provide a foundation for predictive surveillance and rational countermeasure design, enabling earlier detection and more effective containment of future merbecovirus spillover events before they escalate into epidemics.