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. The gene discussed is C21orf58; the disease is hepatocellular carcinoma.