eIF3 musketeers: loyal in health, rogue in disease, and redeemed by therapeutic targeting

Abstract The eukaryotic translation initiation factor 3 (eIF3) is the largest and most complex initiation factor in eukaryotes, functioning as a central hub that integrates signals from cellular stress, metabolism, and developmental pathways to regulate mRNA translation. Recent advances have uncovered subunit-specific roles of eIF3 that extend beyond canonical cap-dependent translation to include specialized mechanisms such as selective mRNA recruitment, noncanonical cap recognition, and translation elongation. This review summarizes the current mechanistic understanding of the contribution of aberrant eIF3 activity to diverse disease processes, including oncogenesis, neurodevelopmental and neurodegenerative disorders, muscle pathology, and infectious disease. We evaluate therapeutic strategies aimed at modulating eIF3 function, including subunit-selective small molecules, RNA-based therapeutics, and CRISPR-based interventions. We discuss the therapeutic promise of both inhibitory approaches—targeting oncogenic or pathogen-hijacked eIF3—and restorative strategies to correct genetic loss-of-function in neurological disease. Finally, we outline key challenges and opportunities for clinical translation, including tissue-specific delivery, subunit selectivity, and the identification of predictive biomarkers. eIF3 emerges as a versatile and druggable node in translational control with broad relevance across human disease.