For a study, researchers sought to investigate the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets using this imaging-genomic surrogate. They used RNA sequencing and whole-exome sequencing data as a discovery cohort from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging. Transcriptomes from the second cohort of 81 patients with more advanced tumors were used to validate the preliminary radiogenic results. According to the PET results, all patients were assigned to an FDG-avid or FDG–non-avid group. In addition, investigators tested potential drug candidates for FDG-avid HCCs in vitro and in vivo. High FDG avidity was associated with a lower recurrence-free survival after HCC resection. Whole-transcriptome analysis revealed that mTOR pathway signals were upregulated in FDG-avid tumors and a higher abundance of associated mutations. In the validation set, these clinical and genomic findings were replicated. In the public-access datasets of 2 cohorts, a molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses. In both the hyperglycolytic HCC cell lines and the xenograft mouse models, treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control. According to our PET-based radiogenic analysis, mTOR pathway genes were significantly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in HCC precision care.