The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular pathogenesis remains incompletely defined in HCC. Here we report that increased expression of alphaB-Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies alphaB-Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We show that elevated expression of alphaB-Crystallin promotes HCC progression in vivo and in vitro. We demonstrate that alphaB-Crystallin overexpression fosters HCC progression by inducing epithelial-mesenchymal transition (EMT) in HCC cells through activation of the extracellular-regulated protein kinase (ERK) cascade, which can counteract the effect of sorafenib. alphaB-Crystallin complexes with and elevates 14-3-3zeta protein, leading to up-regulation of ERK1/2 activity. Moreover, overexpression of alphaB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Clinically, our data reveal that overexpression of both alphaB-Crystallin and 14-3-3zeta correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with alphaB-Crystallin overexpression. Conclusion: These data suggest that the alphaB-Crystallin-14-3-3zeta complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals alphaB-Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (HEPATOLOGY 2013) PUBLICATION ABSTRACT