Clathrin Light Chain B Drives Hepatocellular Carcinoma Progression Through Dual Mechanisms: Small Extracellular Vesicle‐Mediated Angiogenesis and the NF‐κB–PCLAF Signaling Axis

Clathrin light chain B (CLTB) is one of the three light chain subunits of the clathrin complex. This study aims to elucidate the role of CLTB in the pathogenesis of hepatocellular carcinoma (HCC) and its clinical implications. Clinical and bioinformatic analyses reveal marked CLTB overexpression in HCC tissues. Genetic silencing of CLTB suppresses HCC cell proliferation, migration, and invasion, whereas its overexpression exacerbates malignant phenotypes. Mechanistically, CLTB activates NF-κB signaling to upregulate PCNA clamp-associated factor (PCLAF), thereby promoting small extracellular vesicle (sEV) uptake. Given that clathrin-mediated endocytosis is the key mechanism for sEV uptake, this study further investigated the functional implications of CLTB-enriched sEVs in tumor vascular remodeling. sEV-CLTB promotes endothelial angiogenesis, disrupts vascular integrity, and induces pulmonary vascular leakage by binding SH3 domain-containing kinase-binding protein 1 (SH3KBP1) and then inhibiting SH3KBP1 ubiquitination degradation. In patient-derived xenograft (PDX) models, combined therapy of clathrin inhibitor (chlorpromazine) or SH3KBP1 silencing with sorafenib suppresses tumor growth and reduces microvascular density. This study demonstrates that CLTB promotes HCC progression through the NF-κB-PCLAF signaling axis and sEV-mediated vascular remodeling, providing a mechanistic foundation for developing combination therapies targeting CLTB.