RNF123 is an E3 ubiquitin ligase that functions as a catalytic subunit of the KPC complex 12. Its primary role involves promoting ubiquitination and proteasomal degradation of CDKN1B, a cyclin-dependent kinase inhibitor regulating G0-G1 cell cycle transition 12. RNF123 also regulates NF-κB signaling by catalyzing ubiquitination of NFKB1 p105, leading to generation of the active p50 subunit 345. Beyond E3 ligase activity, RNF123 functions as an inhibitor of antiviral signaling through RIG-I and IFIH1 independently of its catalytic activity, competing with MAVS adapter binding 6. Recent studies reveal RNF123 targets additional substrates: PFKP in breast cancer 7, PKM2 in diabetic retinopathy 8, SOCS1 during viral infection 9, and lamin-associated proteins in laminopathies 10. Disease relevance includes roles in cancer progression (downregulated in breast tumors) 7, diabetic retinopathy through glycolytic regulation 8, parasitic infection susceptibility 11, and chr3 widespread pain 12. RNF123 exhibits tissue-specific expression and represents a potential therapeutic target across multiple pathological conditions.