Our study showed that RNF5 inhibition suppresses PEL growth with two types of increased Ephrin type-A receptors, EphA3 and EphA4, and decreased activation of the ERK and Akt pathways, downregulating the expression of multiple cellular pathways and KSHV lytic viral genes, providing a novel choice for PEL therapy and drug development. The gene discussed is EPHA4; the disease is primary effusion lymphoma.