This integrated framework, which conceptualizes the pathway as the central processing unit of a uniquely aggressive immuno-metabolic phenotype, not only illuminates the unique biology of IR/MASH-HCC but also provides new insights and a theoretical basis for the clinical translation of targeting the PI3K/Akt/mTOR pathway—encompassing novel combination strategies and biomarker development—to foster more effective clinical interventions. This evidence concerns the gene MTOR and hepatocellular carcinoma.