Karyopherins in proteostasis and aging

Nucleocytoplasmic transport is a central but underappreciated component of the proteostasis network as it controls the trafficking and partitioning of proteins between the nucleus and cytoplasm through the nuclear pore complex (NPC). Transport of large proteins across the NPC is mediated by karyopherins, a conserved family of importins and exportins that function through a Ran GTPase-dependent cycle. Beyond their canonical transport activities, karyopherins can directly contribute to proteostasis by acting as chaperone-like factors that prevent aberrant phase separation and protein aggregation. Dysregulation of karyopherin-mediated transport emerges as a convergent contributor underlying aging and diverse age-associated diseases, including neurodegeneration, cancer, cardiovascular dysfunction, chronic inflammation, and progeroid syndromes. Here, we highlight how age-related alterations in nucleocytoplasmic transport reshape proteome organization and intracellular signaling, and discuss emerging therapeutic strategies targeting karyopherins to restore proteostasis and cellular homeostasis.