STAT3 and cancer: Many studies found that activation of STAT3 was a common cause of resistance to targeted therapies and chemotherapies in many cancers.[22] STAT3 activation was implied in treatment failure of EGFR/ERK‐targeted and HER‐2‐targeted therapies in various cancers.[23] It was also observed that the sorafenib‐resistant HCC cells highly expressed activated‐STAT3, and STAT3 overactivated HCC was more aggressive and drug‐resistant.[10, 24] Our data showed that C21orf58 was highly expressed in sorafenib‐tolerated HCC cells and positively associated with sorafenib resistance.