CNOT4 is an E3 ubiquitin ligase and component of the CCR4-NOT transcription complex with multifaceted roles in gene regulation and cellular quality control. Functionally, CNOT4 ubiquitinates diverse substrates including methylated RBM15, stalled ribosomes, and the transcriptional regulator PAF1, promoting their degradation via the 26S proteasome 123. Within mitochondrial quality control, CNOT4 ubiquitinates ABCE1 upon mitochondrial damage, recruiting autophagy machinery to initiate mitophagy 4. CNOT4 also regulates mRNA stability through deadenylation pathways; surprisingly, CNOT4 depletion accelerates global mRNA decay while increasing transcription, opposing the effects of core complex scaffold CNOT1 56. Disease relevance is substantial: in hepatocellular carcinoma, CNOT4 degradation via the TNKS1BP1-TRIM21 axis suppresses JAK2/STAT3 signaling, promoting immune evasion and anti-PD-L1 resistance 7. In pancreatic cancer, lncRNA RP11-161H23.5 enhances CNOT4-mediated HLA-A mRNA degradation to evade immune surveillance 8. Conversely, CNOT4 overexpression suppresses non-small cell lung cancer progression 2. CNOT4 also coordinates with ZNF598 in mitochondrial stress-responsive translation quality control, protecting against neurodegeneration 9. These findings establish CNOT4 as a critical node regulating proteostasis, mRNA metabolism, and immune function with significant therapeutic implications across malignancies.