RNF146 is a RING-domain E3 ubiquitin ligase that mediates poly-ADP-ribosylation (PAR)-dependent ubiquitination (PARdU) through its WWE domain, which specifically binds PARylated proteins and targets them for degradation 1. The protein functions as a key regulator of the Wnt/β-catenin signaling pathway by promoting ubiquitination and degradation of PARylated AXIN1 and AXIN2, components of the β-catenin destruction complex, thereby activating Wnt signaling 23. RNF146 undergoes SUMOylation at lysine residues K19 and K175, which promotes its nuclear localization and enhances its interaction with AXIN to accelerate AXIN degradation 3. The protein demonstrates neuroprotective properties and correlates with postoperative delirium and neuroinflammation following anesthesia and surgery 4. In cardiac tissue, RNF146 promotes hypertrophy by targeting LKB1 for ubiquitin-proteasomal degradation, thereby suppressing the protective AMPK signaling pathway 5. Additionally, RNF146 protects against myocardial ischemia/reperfusion injury by promoting ubiquitination-mediated degradation of DAPK1 to inhibit ferroptosis 6. The protein also forms liquid-like condensates with PARP5A to restrain RIPK1-dependent necroptosis through phase separation mechanisms 7. Clinical relevance includes potential therapeutic targeting in hepatocellular carcinoma, where higher RNF146 expression correlates with worse patient prognosis 3.