Taken together, our study not only identifies USP10 as a new prometastatic factor in HCC, but also unravels the mechanistic framework by which USP10 reinforces the TGF‐β signaling through the stabilization of Smad4, thus provides potential therapeutic targets for the treatment against metastatic HCC in Smad4‐positive patients. This evidence concerns the gene USP10 and hepatocellular carcinoma.