Collectively, this study identify systematically uncovers a new mechanism of sorafenib resistance in HCC: RhoE downregulation–mediated activation of the FAK/AKT–cholesterol–SHH/GLI1 axis as a key driver of sorafenib resistance and provide a rationale for combining FAK inhibitors with RAF-targeted therapies and for using cholesterol biosynthesis signatures to guide personalized treatment. Here, SHH is linked to hepatocellular carcinoma.