RNF128 is an X-linked E3 ubiquitin ligase that catalyzes polyubiquitin chain formation (Lys-27, Lys-48, and Lys-63 linkages) and regulates diverse biological processes. Its primary function involves immune modulation: it inhibits IL-2 and IL-4 transcription to promote T-cell anergy 1, while promoting Lys-63-linked ubiquitination of TBK1 during viral infection 2. RNF128 negatively regulates IL-3/STAT5 signaling by targeting IL3RA for degradation 3 and attenuates IL-6-STAT3 signaling by degrading IL-6 receptors 4. Mechanistically, RNF128 targets multiple substrates for degradation including cytoskeletal proteins (ARPC5, cortactin), transmembrane receptors (SRB1, CD40L, CD83), and regulatory proteins (Beclin1, RPN1) 567. It regulates N-glycosylation by ubiquitinating ribophorin I in the endoplasmic reticulum 6. Disease relevance is substantial: RNF128 downregulation promotes melanoma progression and EMT via Wnt pathway activation 8, while elevated expression aggravates atherosclerosis by preventing SRB1 degradation 5. In colorectal cancer, dysbiosis-derived agmatine suppresses RNF128-mediated β-catenin ubiquitination, activating oncogenic Wnt signaling 9. Conversely, RNF128 deficiency promotes colitis and gastric cancer progression 107. RNF128 suppresses gastric cancer by promoting autophagy-dependent ferroptosis through Beclin1 targeting 7.