RNF128 is an X-linked E3 ubiquitin ligase that catalyzes diverse polyubiquitin chain linkages (Lys-27, Lys-48, Lys-63) and regulates immune homeostasis, cytoskeletal dynamics, and metabolic processes. In adaptive immunity, RNF128 inhibits IL-2 and IL-4 transcription to promote T-cell anergy, while in innate immunity it enhances antiviral responses by ubiquitinating TBK1 1. The protein also suppresses pro-inflammatory signaling by targeting TLR4 and IL-6 receptors for degradation, thereby reducing NF-κB activation and STAT3 phosphorylation 2. RNF128 ubiquitinates cytoskeletal proteins (ARPC5, cortactin) and the glycosylation enzyme ribophorin I, affecting lamellipodium formation and N-glycosylation 3. Disease relevance spans colorectal cancer, where downregulation or inhibition of RNF128 promotes tumorigenesis: reduced RNF128 activates Wnt/β-catenin signaling and suppresses ferroptosis via Beclin1 degradation in gastric cancer 4, while commensal-derived agmatine suppresses RNF128-mediated β-catenin ubiquitination to fuel colorectal carcinogenesis 5. Conversely, RNF128 deficiency exacerbates colitis and colitis-associated cancer by impairing IL-6 receptor degradation and S100A8 clearance 26. In atherosclerosis, RNF128 overexpression in macrophages promotes foam cell formation by stabilizing scavenger receptor B1 7. RNF128 is emerging as a therapeutic target for targeted protein degradation via nanobody-based REULR molecules 8.