RNF123 is an E3 ubiquitin ligase that functions as a catalytic component of the KPC complex, regulating cell cycle progression and inflammatory signaling. It promotes ubiquitination and proteasomal degradation of CDKN1B, a cyclin-dependent kinase inhibitor at the G0-G1 transition. RNF123 also regulates NF-κB signaling by catalyzing ubiquitination of NFKB1 p105, generating the active p50 subunit 1. Beyond its canonical E3 ligase activity, RNF123 functions as an inhibitor of innate antiviral signaling mediated by RIG-I and IFIH1 through direct interaction with their CARD domains, competing with the MAVS adaptor independently of its catalytic activity 2. In disease contexts, RNF123 acts as a tumor suppressor in breast cancer by ubiquitinating PFKP to suppress glycolysis and cell proliferation 3, and has been associated with diabetic retinopathy through regulation of PKM2-mediated glycolysis in Müller cells 4. Genome-wide association studies identified RNF123 variants associated with chr3 widespread musculoskeletal pain in Northern Europeans 5, and genetic analyses link RNF123 to depression-related dysmenorrhea and smoking-related gastroesophageal reflux disease. At the population level, RNF123 shows LoF tolerance; however, these associations suggest meaningful pathogenic roles in specific disease contexts.