RNF5 is a membrane-bound E3 ubiquitin-protein ligase that catalyzes K48-linked and K63-linked polyubiquitination of diverse target proteins, functioning with E2 enzymes UBE2D1/UBCH5A and UBE2D2/UBC4 1. RNF5 mediates ubiquitination of paxillin to regulate cell motility 2, ubiquitinates JKAMP via K63-linked chains 3, and catalyzes K48-linked ubiquitination of STING1 at mitochondria following viral infection to suppress antiviral responses 4. Additionally, RNF5 ubiquitinates and degrades ATG4B to inhibit autophagy 5. RNF5 plays critical roles in disease pathogenesis: elevated expression correlates with poor prognosis in acute myeloid leukemia (AML), where RNF5 controls epigenetic regulation through RBBP4 ubiquitination and K29-chain formation 6. RNF5 is highly expressed in liver cancer 7 and facilitates gastric cancer progression by stabilizing ATG2B 8. Functionally, RNF5 restricts SARS-CoV-2 replication by degrading the envelope protein 9 and inhibits foot-and-mouth disease virus through VP1 ubiquitination 10. RNF5 also exerts protective effects in immune thrombocytopenia by modulating platelet-related proteins 11. These multifaceted functions establish RNF5 as a therapeutic target for viral infections, cancer, and autoimmune disorders.