TCF25 is a multifunctional protein serving as a component of the ribosome quality control (RQC) complex and a nutrient sensor. As an RQC complex subunit, TCF25 promotes K48-linked polyubiquitin chain formation during ubiquitination of incompletely synthesized nascent chains by the E3 ligase Listerin, facilitating their proteasomal degradation 1. Mechanistically, TCF25 directly binds the acceptor ubiquitin and orients it to position K48 optimally for conjugation to nascent chains 2. Beyond ribosomal quality control, TCF25 functions as a nutrient sensor that enhances lysosomal acidification via V-ATPase targeting under glucose starvation, promoting autophagy and ATP generation 3. However, prolonged starvation activates ferritinophagy through TCF25, increasing lysosomal membrane permeability and triggering lysosome-dependent cell death 3. In Plasmodium falciparum, TCF25 acts as a transcriptional regulator controlling ribosomal biogenesis and gametocytogenesis 4. Clinically, TCF25 dysregulation associates with age-related hearing loss via altered DNA methylation 5 and colorectal cancer progression, particularly left-sided colon cancer 6. TCF25 deficiency protects against hepatic ischemia-reperfusion injury, suggesting therapeutic potential in metabolic and ischemic disorders 3.