SNX8 regulates BMPR2-mediated SMAD5 proteostasis to drive epithelial-mesenchymal transition in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by high metastasis and poor prognosis. While the sorting nexin (SNX) family is linked to tumorigenesis, the role of SNX8 in HCC remains unexplored. METHODS: SNX8 expression and prognostic value were validated using TCGA datasets and clinical tissues. The impact of SNX8 on malignant phenotypes was evaluated via in vitro assays and in vivo xenograft models. RNA-seq was conducted to elucidate underlying mechanisms, followed by rescue experiments using pharmacological agents and plasmid transfection to verify key proteins. RESULTS: SNX8 is significantly overexpressed in HCC and predicts poor patient prognosis. Mechanistically, SNX8 facilitates BMPR2 sorting and trafficking to the cell membrane, enabling SMAD5 phosphorylation and nuclear translocation of the p-SMAD5/SMAD4 complex to activate SNAIL1-mediated Epithelial-mesenchymal transition (EMT). Conversely, SNX8 inhibition causes abnormal intracellular accumulation of BMPR2, leading to the ubiquitin-proteasome degradation of SMAD5 due to its failed recruitment to the receptor. Overexpressing SMAD5 successfully rescues the impaired proliferation and migration induced by SNX8 silencing. CONCLUSION: Our study identifies SNX8 as a novel oncogenic regulator that promotes EMT and metastasis in HCC by stabilizing SMAD5 through the BMPR2 signaling axis. These findings highlight the SNX8/SMAD5 axis as a potential therapeutic target for advanced HCC.