RNF34 is an E3 ubiquitin ligase that negatively regulates multiple cellular processes through K48-linked polyubiquitination and proteasomal degradation of target proteins. Primary targets include caspases 8 and 10, where RNF34-mediated degradation suppresses extrinsic apoptotic signaling 1. RNF34 also targets PGC-1α, the master regulator of mitochondrial biogenesis; in glioma cells, DNA-dependent protein kinase-mediated phosphorylation of PGC-1α at serine 636 enhances RNF34 binding and degradation, promoting radiotherapy resistance through suppressed mitochondrial metabolism 2. Conversely, KMT5C inhibits this interaction, protecting PGC-1α and promoting hepatic gluconeogenesis 3. In vascular smooth muscle, RNF34 ubiquitinates and degrades p22phox, controlling NADPH oxidase activity; RNF34 loss increases ROS generation and promotes hypertension and cerebrovascular remodeling 4. RNF34 also regulates innate immunity by catalyzing K27/K29-linked ubiquitination of MAVS, facilitating autophagic degradation and clearing damaged mitochondria during viral infection 5. Additionally, RNF34 mediates FliI ubiquitination on inflammasome-containing endosomes, enhancing NLRP3 inflammasome activity 6. Clinically, elevated RNF34 expression correlates with poor prognosis in Wilms' tumor but predicts chemotherapy sensitivity 7.