RNF126 is an E3 ubiquitin-protein ligase that mediates polyubiquitination of target proteins through 'Lys-27', 'Lys-29', 'Lys-48' and 'Lys-63' linkages 1. The protein functions as a critical regulator of DNA damage response by ubiquitinating MRE11 at K339 and K480, enhancing its exonuclease activity and promoting homologous recombination repair 1. RNF126 participates in protein quality control by associating with the BAG6 complex to target mislocalized secretory proteins for proteasomal degradation 2. Additionally, it regulates mitochondrial protein homeostasis by interacting with UBQLN1 to facilitate degradation of unimported mitochondrial membrane proteins 2. RNF126 also controls ferroptosis by ubiquitinating ferroptosis suppressor protein 1 (FSP1), affecting its plasma membrane localization 3. Clinically, RNF126 overexpression is associated with poor prognosis in multiple cancers including triple-negative breast cancer, gastric cancer, hepatocellular carcinoma, and prostate cancer 456. In hepatocellular carcinoma, RNF126 promotes stem cell-like properties and metastasis by ubiquitinating and degrading tumor suppressor LKB1 5. The protein's expression is regulated by multiple signaling pathways including HER2-AKT-NF-κB, making it a potential therapeutic target 17.