STAT3 and hepatocellular carcinoma: In this study, we clarified the oncogenic biofunction of C21orf58, illuminated the underlying molecular mechanism of prompting growth, tumorigenesis, and sorafenib resistance mediated by C21orf58 in HCC cells, identified a new adaptor and a novel regulation mechanism of STAT3 signaling, explained the cause of hyper‐activation of STAT3 driven by constitutive mutations, and evaluated the therapeutic potential of targeting C21orf58 in HCC.