Regulatory roles of E3 ubiquitin ligase RNF128 in inflammatory diseases and tumors.

Ring finger protein 128 (RNF128) belongs to the family of transmembrane E3 ubiquitin (Ub) ligases. It mediates substrate-specific ubiquitination as a critical post-translational modification and regulates diverse physiological activities and pathological processes. More importantly, the E3 Ub ligase RNF128 is involved in both innate and adaptive immune responses through ‌Ub-dependent regulation‌ of its target proteins. Dysregulation of RNF128 is associated with the occurrence and development of multiple diseases. In recent years, numerous studies have demonstrated the involvement of RNF128 in the progression of inflammatory disorders and tumors. Nevertheless, mechanistic discrepancies persist regarding its dual pro-/anti-inflammatory and pro-/anti-tumor functions. Furthermore, there remains a lack of systematic evaluation concerning the ‌context-dependent regulatory roles of RNF128 in inflammatory responses and tumorigenesis, as well as its targeted therapeutic landscape. Accordingly, this article comprehensively reviews the structure-function relationships of RNF128, its mechanistic regulation of inflammation and tumor progression, and the existing functional controversies in colorectal cancer. It summarizes potential targeted intervention strategies and clinical translational prospects, highlights current research limitations, and proposes future investigative directions. This review aims to provide scientific references for further mechanistic exploration of RNF128 and the development of precision therapeutic strategies for related diseases.