Hepatitis E virus (HEV) causes an estimated 20 million annual human infections, resulting in approximately 70,000 related deaths. HEV has a diverse host-range and novel zoonotic events are of global concern. As such, HEV was ranked sixth during an evaluation of all animal viruses which pose the greatest risk for new human spillover. Although HEV emergence is increasing, many molecular aspects of the infectivity are poorly characterised. The proteasome has previously been identified as a key host-cell pathway during HEV infection, however the molecular mechanisms underpinning this requirement remain unclear. Here, we sought to elucidate the viral component(s) affected by proteasomal dysregulation. Additionally, we aimed to determine which stage(s) of the HEV lifecycle depends on the proteasome. Using HEV sub-genomic replicons and the FDA-approved proteasome inhibitor bortezomib, we confirm a dependence on proteasome function for efficient HEV genome replication. Interestingly, addition of bortezomib resulted in decreased expression of the HEV non-structural polyprotein (pORF1), suggesting a potential role in viral protein translation or polyprotein processing. We also report that HEV proteasomal dependence is conserved between a variety of different genotypes and host cells.   Further experiments are underway to elucidate how the proteasome influences HEV pORF1 synthesis and genome replication. We propose that HEV pORF1 utilises the proteasomal network allowing continued viral protein synthesis during chronic infection. Understanding the dependence of host-cell machinery during HEV replication may aid in the repurposing of FDA-approved compounds which act as host-targeted antivirals, and can be utilised as novel therapeutics.