Collectively, this work establishes the TTC36/YBX3/SPRED1 axis as a fundamental regulator of HCC proliferation and provides critical insights into the interplay between tumor suppression and therapeutic efficacy, offering a foundation for TTC36-based patient stratification and personalized therapy (e.g., Sorafenib and Akt inhibitor combinations). Here, AKT1 is linked to hepatocellular carcinoma.