eIF3i facilitates NELFCD translation to promote metastasis via regulating EMT and invadopodia.

BackgroundTranslational reprogramming enables cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear.MethodsProteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases.ResultseIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases.ConclusionsThe eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.