RNF25 is an E3 ubiquitin ligase functioning as a critical hub in multiple cellular quality control and signaling pathways. Canonically, RNF25 operates within a ribosomal quality control network alongside RNF14, catalyzing ubiquitination of ribosomal proteins (RPS27A, RPL0, RPL1, RPL12, RPS13, RPS17) and translation factors (eEF1A, eRF1) on stalled ribosomes to promote their proteasomal degradation 1. This pathway is activated by ribosome collisions and helps maintain proteostasis during translational stress, including resolution of RNA-protein crosslinks 2. Beyond translation quality control, RNF25 participates in diverse cellular processes. It mediates ubiquitination and degradation of ACSL4 in ferroptosis regulation 3, E-cadherin in hepatocellular carcinoma metastasis 4, and FKBP8 to promote colorectal cancer liver metastasis 5. RNF25 also functions in DNA replication stress tolerance through a REV7-dependent mechanism independent of ubiquitin conjugation 6. Clinically, RNF25 drives cancer drug resistance through NF-κB pathway activation. It promotes gefitinib resistance in EGFR-mutant NSCLC 7 and renal cell carcinoma apoptosis resistance 8, making RNF25 an emerging therapeutic target for overcoming treatment resistance across multiple malignancies.