Our results show that KSHV-positive PEL cells generate more aggressive tumorigenesis in NOD/SCID mice than non-KSHV-infected lymphoma cells, and RNF5 silence significantly suppresses xenograft tumor growth of KSHV-positive PEL cells in NOD/SCID mice, while slightly affects in vivo growth of non-KSHV-infected lymphoma cells (Fig 8C and 8D), because RNF5 inhibition not only suppresses tumor cell growth and tumorigenesis through multiple pathways, but also effectively disrupts KSHV lytic replication and consequent KSHV-induced the expression of cytokines and inflammatory factors. Here, RNF5 is linked to lymphoma.