Rubicon as an emerging regulator in the interplay between mpox virus infection and autophagy

Mpox virus (MPXV) has recently emerged as a major global public health concern, underscoring the need to better understand the molecular mechanisms governing virus–host interactions. Like other members of the Orthopoxvirus genus, MPXV relies extensively on host cellular pathways to complete its replication cycle while simultaneously counteracting cellular antiviral mechanisms. Among these host pathways, autophagy has attracted increasing attention because of its dual role in maintaining cellular homeostasis and restricting intracellular pathogens through lysosomal degradation. Recent evidence has identified Rubicon (RUN domain Beclin-1-interacting and cysteine-rich domain-containing protein) as a central regulator at the interface between autophagy and viral infection. By negatively regulating canonical autophagy while simultaneously participating in non-canonical pathways, Rubicon occupies a unique position in the control of intracellular membrane trafficking and innate immune responses. Importantly, a growing number of viruses have evolved mechanisms to exploit Rubicon-dependent pathways, highlighting this protein as a potentially conserved target of viral immune evasion. In this review, we summarize current knowledge of the interplay between orthopoxviruses and the autophagic machinery, with a focus on MPXV and Rubicon as a key negative regulator of autophagy and a potential modulator of viral pathogenesis. We also discuss the broader role of Rubicon in viral infections and consider its potential as a therapeutic target for the development of host-directed antiviral strategies.