Clathrin Light Chain B (CLTB) drives hepatocellular carcinoma progression through dual pathways: intracellularly, it activates the NF‐κB–PCLAF axis to enhance small extracellular vesicle (sEV) uptake and tumor proliferation; extracellularly, CLTB‐enriched sEVs bind SH3KBP1 to inhibit its degradation, inducing angiogenesis and vascular leakage. This evidence concerns the gene NFKB1 and hepatocellular carcinoma.