Notably, depletion of EphA3 or EphA4 recovered ERK and Akt activation and lytic gene expression in RNF5 KO BCBL1 cells or RNF5-depleted iSLK.219 cells as well as the cell cycle-dependent kinase CDK1 and hedgehog gene Smo expression, indicating that these two novel substrates are involved in PEL suppression by RNF5 inhibition, and their interplay and function should be identified in further investigations to develop their potential application in PEL treatment. This evidence concerns the gene SMO and primary effusion lymphoma.