Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumour-stroma crosstalk in experimental models

•NAE1-dependent protein NEDDylation is increased in human cholangiocarcinoma.•NEDDylation contributes to cholangiocarcinogenesis favoring pro-survival mechanisms.•Abnormal NEDDylation alters the cholangiocarcinoma secretome, impacting on the stroma crosstalk.•Molecular and pharmacological targeting of NAE1 halts experimental tumor growth.•NAE1 inhibition with pevonedistat is a promising therapy for patients with cholangiocarcinoma.