RNF5 is a membrane-bound E3 ubiquitin ligase that catalyzes both K48- and K63-linked polyubiquitination of diverse substrates. The enzyme functions with E2 conjugating enzymes including UBE2D1/UBCH5A, UBE2D2/UBC4, and UBE2N to regulate cell motility, innate immunity, and metabolic homeostasis. RNF5 mediates ubiquitination of paxillin to control cell localization and motility, and catalyzes K48-linked polyubiquitination of STING1 at the mitochondria after viral infection, negatively regulating antiviral responses 1. The ligase also inhibits autophagy by promoting ATG4B degradation and restricts SARS-CoV-2 replication by targeting its envelope protein 2. In acute myeloid leukemia, elevated RNF5 expression correlates with poor prognosis and drives disease through K29-linked ubiquitination of the histone-binding protein RBBP4, an ERAD-independent epigenetic pathway 3. RNF5 expression is upregulated in liver cancer 4 and ameliorates nonalcoholic steatohepatitis by promoting HRD1 degradation 5. Emerging evidence suggests RNF5 activation via small molecules such as Analog-1 and lasalocid A may offer therapeutic benefit: Analog-1 alleviates SARS-CoV-2 and foot-and-mouth disease virus infection 26, while lasalocid A selectively degrades mutant MYD88 L265P in lymphomas and synergizes with venetoclax 7.