This study identifies CLTB as a key driver of HCC progression through dual mechanisms: the intracellular activation of the NF‐κB–PCLAF signaling axis facilitates sEV uptake and promotes tumor cell proliferation, while concurrently mediating vascular remodeling by stabilizing the SH3KBP1 protein through the inhibition of ubiquitination‐mediated degradation. This evidence concerns the gene SH3KBP1 and neoplasm.