Eif4g2, also known as DAP5, Nat1, p97, is a eukaryotic translation initiation factor. It's a member of the eIF4G family but lacks binding sites for 5' cap-binding protein eIF4E. Eif4g2 is involved in non-canonical translation initiation mechanisms, especially in leaky scanning through upstream open reading frames (uORFs) in long 5' UTRs of mRNAs from higher eukaryotes. It may help ribosomes overcome impediments during 5' UTR scanning, which is crucial as many regulatory protein-encoding mRNAs in higher eukaryotes have long and structured 5' UTRs [2].

In neuronal cells, depolarization leads to phosphorylation and recruitment of eIF4G2. This is accompanied by increased translation of uORFs and their downstream coding sequences for proteins involved in long-term potentiation, cell signaling, and energy metabolism. Thus, eIF4G2 couples neuronal activity to local dendritic remodeling through activity-dependent uORF translational control [1].

In hepatocellular carcinoma (HCC), Eif4G2 is significantly upregulated and associated with poor prognosis. Deletion of Eif4G2 suppresses tumor growth and metastasis in vitro and in vivo. Eif4G2 regulates protein translation, specifically facilitating PLEKHA1 translation via an IRES-dependent manner, highlighting its role in HCC malignancy [3].

In osteosarcoma, Eif4G2, identified from an RNA-modification-related signature, promotes tumor proliferation, migration, and M2 macrophage migration, suggesting it as a critical immunotherapy determinant [4].

In conclusion, Eif4G2 plays essential roles in translation initiation, especially in non-canonical pathways like leaky scanning. Studies using loss-of-function models, such as deletion in HCC and analysis in osteosarcoma, have revealed its significance in cancer-related processes. In neurons, it is crucial for activity-dependent dendritic remodeling. These findings emphasize Eif4G2 as a key factor in understanding biological processes and developing potential therapeutic strategies for related diseases.