Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis

Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.