RNF34 is an E3 ubiquitin ligase that negatively regulates multiple cellular pathways through proteasomal degradation of target proteins. It ubiquitinates caspases CASP8 and CASP10 to suppress extrinsic apoptosis, directly ubiquitinates p53 to attenuate tumor suppressor signaling, and promotes degradation of PGC-1α (PPARGC1A), a master regulator of mitochondrial biogenesis. In skeletal muscle, RNF34 inhibition increases mitochondrial biogenesis and extends exercise capacity 1. RNF34 also regulates innate immunity by mediating K27- and K29-linked ubiquitination of MAVS, targeting it for autophagic degradation after viral infection 2. In vascular smooth muscle cells, RNF34 loss promotes hypertension and cerebrovascular remodeling by increasing NADPH oxidase-derived reactive oxygen species through stabilization of p22phox 3. Recent findings identify RNF34 as part of a signaling complex with ZFYVE21 and Rubicon that promotes inflammasome assembly on endosomes 4. Clinically, elevated RNF34 expression in Wilms' tumour correlates with poor prognosis but increased chemotherapy sensitivity 5. In gliomas, radiotherapy induces RNF34-mediated PGC-1α degradation to suppress mitochondrial biogenesis and drive radioresistance; PGC-1α activators or phosphorylation-resistant mutants restore radiosensitivity 6.