RNF5: an emerging therapeutic target for modulating immunity and metabolism

Ring finger protein 5 (RNF5), a membrane-associated RING-type E3 ubiquitin ligase, serves as a critical regulator of cellular homeostasis by controlling protein stability, metabolic adaptation, and immune signaling. This review provides a comprehensive overview of the multifaceted functions of RNF5, with particular emphasis on its context-dependent roles in cancer progression, antiviral immunity, and non-neoplastic diseases. In cancer, RNF5 exhibits highly context-dependent and sometimes paradoxical functions that are influenced by cellular environments, disease stages, and substrate availability. RNF5 regulates tumor-associated metabolic reprogramming by targeting glutamine transporters and key regulators of lipid metabolism. Moreover, through interactions with autophagy-related proteins and Ephrin receptors, RNF5 modulates tumor growth, therapeutic resistance, and antitumor immune responses. These findings highlight RNF5 as a complex regulator of tumor biology with both oncogenic and tumor-suppressive potential. During viral infections, RNF5 demonstrates dual regulatory activities in host-pathogen interactions. On one hand, RNF5 can suppress antiviral innate immune signaling by promoting the ubiquitination and degradation of key immune adaptors, including STING and MAVS. On the other hand, RNF5 may restrict viral replication by directly targeting viral components, such as the SARS-CoV-2 envelope protein and foot-and-mouth disease virus VP1, for ubiquitination and degradation. Thus, RNF5 functions as a versatile modulator of antiviral defense, with effects determined by the specific viral context and host signaling landscape. Beyond cancer and viral infection, emerging evidence implicates RNF5 in a variety of non-neoplastic disorders. RNF5 contributes to protein quality control in neurodegenerative diseases by facilitating the clearance of pathological tau through the ERAD pathway. In addition, genetic inhibition of RNF5 ameliorates intestinal pathological phenotypes in a mouse model of cystic fibrosis, while RNF5 has also been associated with hepatic and cardiovascular injury responses through regulation of cellular stress pathways. From a therapeutic perspective, RNF5-targeting strategies, including small-molecule inhibitors and pathway modulators, have emerged as potential approaches for manipulating RNF5-associated biological processes. However, substantial challenges remain, including achieving target specificity, understanding the context-dependent consequences of RNF5 modulation, minimizing potential disruptions to proteostasis and innate immune regulation, and developing clinically feasible therapeutic interventions. This review summarizes the complex regulatory network governed by RNF5 and discusses future opportunities and challenges in translating mechanistic insights into therapeutic applications while carefully considering potential risks associated with RNF5 targeting.