KPNA4 (karyopherin subunit alpha 4) is a nuclear import receptor that mediates the transport of cargo proteins into the nucleus through recognition of nuclear localization signals (NLS). Primary function: KPNA4 facilitates NLS-dependent protein nuclear import 1, including non-classical NLS-bearing substrates such as human cytomegalovirus UL84 and the RNA-binding protein TDP-43 2. Mechanism: KPNA4 selectively interacts with the NLS of TDP-43 and mediates nucleocytoplasmic shuttling of transcription factors including NF-κB 3. Disease relevance: KPNA4 pathology is a molecular signature of ALS and frontotemporal dementia, where cytoplasmic TDP-43 accumulation causes KPNA4 mislocalisation and nuclear depletion 2. Germline variants near KPNA4 confer strong associations with clonal hematopoiesis of indeterminate potential (CHIP), a predisposition to hematological malignancy and cardiovascular disease 4. Clinical significance: Elevated KPNA4 expression serves as an independent prognostic risk factor in hepatocellular carcinoma, correlating with immune cell infiltration and T cell exhaustion 5. KPNA4 knockdown reduces prostate cancer metastasis by altering tumor microenvironment through TNF-α/β modulation 3. KPNA4 functions in lupus nephritis by regulating mesenchymal stem cell migration via the CXCL10-CXCR3 pathway 6.