RNF135 is an E3 ubiquitin ligase with dual roles in antiviral immunity and oncogenic signaling. In antiviral defense, RNF135 functions as a RIG-I coreceptor that catalyzes Lys-63-linked polyubiquitination of RIG-I oligomerized on viral RNAs, activating the RIG-I signaling pathway and antiviral innate immune responses 1234. Beyond ubiquitin-dependent mechanisms, RNF135 bridges RIG-I filaments on longer viral RNAs, enabling RNA length-dependent pathway regulation 4. In cancer, RNF135 is significantly upregulated in multiple malignancies. In glioblastoma, RNF135 promotes proliferation via the ERK pathway and p21 ubiquitin-mediated degradation 56, while in osteosarcoma and lung adenocarcinoma, it activates PI3K/AKT and ULK1-mediated autophagy pathways respectively 78. RNF135 methylation serves as a sensitive HCC detection biomarker in circulating cell-free DNA 9. Additionally, RNF135 haploinsufficiency correlates with overgrowth in NF1 microdeletion syndrome, suggesting previously unknown developmental mechanisms 10. However, disease association of RNF135 in developmental disorders has been refuted in large population studies 11.