{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KPNA5 (karyopherin α5) is a nuclear transport receptor that recognizes classical nuclear localization signals (NLS) and mediates the import of target proteins into the nucleus—a function that is pivotal for regulating key cellular processes ranging from metabolic adaptations and gene expression to immune signaling and tumor suppression. Under conditions of metabolic stress, for example, KPNA5 binds to ACSS2 once its NLS is exposed via AMP‐activated mechanisms, facilitating ACSS2’s nuclear translocation where it supports local histone acetylation, autophagy, and tumor progression in brain tumors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of viral infections, multiple studies demonstrate that filoviral proteins—most notably Ebola virus VP24 and Lloviu virus VP24—exploit KPNA5. These viral proteins bind to a unique, nonclassical NLS‐binding site on KPNA5 with high affinity, thereby competitively inhibiting the nuclear import of phosphorylated STAT1 and suppressing the type I interferon response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " Computational and experimental studies further support that destabilizing the VP24–KPNA5 interaction can restore immune signaling, providing a promising strategy for antiviral intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in viral immune evasion, KPNA5 has been implicated in cancer. Somatic mutations in KPNA5 have been identified in breast cancers, underscoring its potential contribution to tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, KPNA5 facilitates the estrogen‐dependent nuclear import of the tumor suppressor prohibitin 2 (PHB2), a process that is inhibited by the protein BIG3 in breast cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", suggesting that dysregulation of KPNA5‐mediated transport may contribute to endocrine therapy resistance and cancer progression. A broader proteomic analysis in anthracycline‐resistant breast cancer cells further identified KPNA5 among key interacting proteins associated with drug resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies highlight the multifaceted role of KPNA5 in orchestrating nuclear import events that are critical for metabolic adaptation, immune surveillance, and cellular homeostasis. Its exploitation by viruses to blunt interferon signaling and its mutation or misregulation in cancer underscore KPNA5 as both a fundamental mediator of cellular function and a candidate therapeutic target in diverse disease contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xinjian Li, Willie Yu, Xu Qian, et al. 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