RNF181 is an E3 ubiquitin ligase that catalyzes protein ubiquitination by accepting ubiquitin from E2 conjugating enzymes and transferring it to substrates 1. Beyond its canonical role in proteasomal degradation, including monoubiquitination of proteasome subunit PSMC2/RPT1 2, RNF181 exhibits context-dependent regulatory functions through non-degradative ubiquitination. Mechanistically, RNF181 stabilizes estrogen receptor alpha (ERα) through K63-linked polyubiquitination, enhancing ERα protein levels and target gene expression in breast cancer cells 3. This stabilization function is facilitated by circRNA-SFMBT2, which recruits RNF181 to ERα's AF1 domain 4. Additionally, RNF181 negatively regulates NF-κB signaling by ubiquitinating Bcl10 downstream of CARD11 in lymphocytes, limiting aberrant proliferation in diffuse large B cell lymphoma 5. RNF181 also promotes ubiquitin-mediated degradation of ATG7, suppressing autophagy and enhancing anti-tumor immunity in lung adenocarcinoma 6. Clinically, elevated RNF181 expression correlates with poor prognosis in ER+ breast cancer and is linked to endocrine resistance 34. RNF181 was identified as a potential biomarker for coronary artery disease in cardiac tissue 7. RNF181's activity is modulated by S-nitrosylation, providing post-translational regulation of its ubiquitin ligase function 8.