SCAMP3: a two-front driver of hepatocellular carcinoma via YAP activation and extracellular vesicle export

Abstract Single-cell transcriptomic analysis of primary hepatocellular carcinoma (HCC) revealed that SCAMP3 is predominantly expressed in metabolically aberrant malignant hepatocyte clusters. Despite its known roles in vesicle transport and extracellular microenvironment regulation, the comprehensive function of SCAMP3 in HCC progression has been largely overlooked. In this study, we demonstrate that SCAMP3 enhances oxidative phosphorylation and shifts fuel substrate preference toward glucose utilization. Mechanistically, SCAMP3 promotes the degradation of LATS1 and MST1, facilitates YAP nuclear translocation, and activates downstream gene transcription, thereby accelerating HCC progression. Additionally, SCAMP3 boosts extracellular vesicle (EV) production and binds to YAP, mediating its incorporation into EVs. These SCAMP3-enriched EVs enhance the proliferation and migration of recipient hepatocytes. Notably, the YAP inhibitor Super-TDU antagonizes both the intracellular and extracellular oncogenic effects of SCAMP3 in vitro and in vivo. Proteomic profiling of EVs further indicates that SCAMP3 remodels the tumor immune microenvironment. Collectively, these findings establish SCAMP3 as a key regulator of HCC progression through a novel intracellular YAP-dependent mechanism and an EV-mediated intercellular route for disseminating malignant signals. SCAMP3 thus represents a promising diagnostic and prognostic biomarker, as well as a potential therapeutic and immunomodulatory target for HCC.