CNOT6L is a catalytic subunit of the CCR4-NOT complex with 3'-5' poly(A) exoribonuclease activity that functions as a major mRNA deadenylase 1. It catalyzes poly(A) tail shortening of target mRNAs, likely through interaction with 3'-UTR cis-elements, thereby regulating mRNA stability and expression levels across multiple physiological processes 2. CNOT6L mediates diverse cellular functions through deadenylation-dependent mRNA decay. In metabolic homeostasis, CNOT6L suppresses hepatokine expression (GDF15 and FGF21) to modulate food intake and energy expenditure; CNOT6L inhibition stabilizes these mRNAs and ameliorates diet-induced metabolic syndrome 3. In cardiac physiology, CNOT6L prevents heart failure progression by downregulating tenascin-C mRNA in cardiac fibroblasts, thereby suppressing fibrosis and inflammation 2. In skeletal muscle, CNOT6L regulates myogenesis through post-transcriptional repression of IL-8 4. CNOT6L promotes cell proliferation and survival while preventing cellular senescence 1, though elevated expression correlates with poor outcomes in type 2 diabetes and triple-negative breast cancer 56. CNOT6L expression is regulated by the E3 ubiquitin ligase RNF219, which targets it for proteasomal degradation 6. These findings establish CNOT6L as a critical regulator of gene expression with therapeutic potential in metabolic and cardiovascular diseases.