SH3RF2 is an E3 ubiquitin ligase that functions as an oncogenic regulator of cellular survival and proliferation. Structurally, it contains three SH3 domains and RING domains critical for its enzymatic activity 1. Primary functions include promoting cell survival through ubiquitin-mediated protein degradation: it stabilizes PAK4 by inhibiting its ubiquitination 2 and acts as an anti-apoptotic regulator by ubiquitinating and degrading POSH, a scaffold protein required for pro-apoptotic JNK activation 3. SH3RF2 also facilitates TNF-mediated signaling and inhibits PPP1CA phosphatase activity 2. In disease contexts, SH3RF2 is frequently overexpressed in multiple cancers. In lung squamous cell carcinoma, elevated SH3RF2 promotes tumor progression and M2 macrophage polarization through LZTS2 ubiquitination and β-catenin signaling 1. In ovarian cancer, SH3RF2 drives cisplatin resistance by degrading RBPMS, an inhibitor of drug resistance 4. Conversely, SH3RF2 deficiency aggravates non-alcoholic fatty liver disease by impairing ATP citrate lyase degradation and promoting lipogenesis 5. In colorectal cancer, low SH3RF2 expression correlates with improved survival 6. These findings establish SH3RF2 as a context-dependent oncogenic regulator and potential therapeutic target for cancer and metabolic disease.