XPO4 (exportin 4) is a nuclear export receptor that mediates the cytoplasmic transport of multiple cargo proteins. XPO4 functions by binding cooperatively in the nucleus to cargo proteins—including EIF5A, SMAD3, and PKM2 isoform M2—and to active Ran-GTP, forming a trimeric complex that docks at nuclear pore complexes through nucleoporin interactions 12. Upon cytoplasmic transit, Ran-GTP hydrolysis to Ran-GDP causes complex disassembly and cargo release, allowing XPO4 recycling for subsequent export rounds 12. Structurally, XPO4 recognizes the hypusinated amino acid on EIF5A through a deep acidic pocket, enabling cargo-specific recognition 3. Clinically, XPO4 dysfunction is implicated in liver disease pathogenesis. Decreased XPO4 expression correlates with poor hepatocellular carcinoma (HCC) prognosis and serves as an independent survival predictor 4. XPO4 promoter hypermethylation suppresses transcription during HBV-induced HCC progression and liver fibrosis development 56. XPO4 copy number duplications increase non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) risk, with reduced serum XPO4 levels correlating to disease severity 78. Mechanistically in fibrosis, reduced XPO4 sustains SMAD3 nuclear accumulation, promoting fibroblast activation via TGF-β signaling 8. Additionally, XPO4 knockout modulates enzalutamide response in castration-resistant prostate cancer 9, suggesting broader therapeutic relevance beyond hepatic diseases.