We found that selective RNF5 inhibition suppresses KSHV lytic replication and PEL tumorigenesis by increasing EphA3 and EphA4 levels and then disrupting ERK and Akt activation, hedgehog and cell cycle gene expression, and KSHV lytic replication, indicating that RNF5 plays the essential roles in KSHV lytic infection and PEL treatment. The gene discussed is RNF5; the disease is primary effusion lymphoma.