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Diabetes is a major risk factor in the development and progression of several cancers including cholangiocarcinoma (CCA). However, the molecular mechanism by which hyperglycemia potentiates progression of CCA is not clearly understood. Here, we showed that a high glucose condition significantly increased reactive oxygen species (ROS) production and promoted aggressive phenotypes of CCA cells, including proliferation and migration activities. Mannosidase alpha class 2a member 2 (MAN2A2), was upregulated at both mRNA and protein levels in a high glucose‐ and ROS‐dependent manner. In addition, cell proliferation and migration were significantly reduced by  MAN2A2  knockdown. Based on our proteome and in silico analyses, we further found that chromodomain helicase DNA‐binding protein 8 ( CHD8 ) was induced by ROS signaling and regulated  MAN2A2  expression. Overexpression of CHD8 increased  MAN2A2  expression, while  CHD8  knockdown dramatically reduced proliferation and migration as well as  MAN2A2  expression in CCA cells. Moreover, both  MAN2A2  and  CHD8  were highly expressed with positive correlation in CCA tumor tissues. Collectively, these data suggested that high glucose conditions promote CCA progression through ROS‐mediated upregulation of  MAN2A2  and  CHD8 . Thus, glucose metabolism is a promising therapeutic target to control tumor progression in patients with CCA and diabetes.

High glucose‐ROS conditions enhance the progression in cholangiocarcinoma via upregulation of MAN2A2 and CHD8