EIF4G2 is a non-canonical eukaryotic translation initiation factor that facilitates cap-independent protein synthesis through multiple mechanisms. Unlike its homologue eIF4G1, EIF4G2 lacks eIF4E-binding sites and functions primarily in IRES-mediated translation 1. EIF4G2 plays crucial roles in translating upstream open reading frames (uORFs), promoting both leaky scanning and reinitiation mechanisms that enable downstream ORF translation 2. Additionally, EIF4G2 mediates m6A-driven translation of circular RNAs, working in conjunction with the m6A reader YTHDF3 to initiate protein synthesis from these non-canonical substrates 34. In neurons, EIF4G2 undergoes phosphorylation and recruitment to regulate activity-dependent dendritic translation of uORF-containing mRNAs involved in synaptic plasticity 5. Disease relevance includes cancer progression: EIF4G2 overexpression is associated with tamoxifen resistance in breast cancer through selective translation of MCL1 mRNA 6, and elevated EIF4G2 enables colorectal cancer liver metastasis via m6A-mediated circ-YAP translation 4. Osteosarcoma cell proliferation and invasion depend on EIF4G2, as miR-379-mediated EIF4G2 downregulation reduces these malignant phenotypes 7. Clinically, engineered circRNA-LNP therapeutics targeting EIF4G2+ cancers show promise in preventing adenocarcinoma development 8. These findings establish EIF4G2 as a multifunctional regulator of translation with significant implications for cancer biology and therapeutic development.