As a result, we continued to analyze the activation of the PI3K/Akt signaling pathway in HCC cells grown on different-stiffness substrates and found that increased matrix stiffness evidently activated the PI3K/Akt signaling pathway (Figure 3B), illustrating that a common pathway of PTEN/PI3K/Akt/MMPs activated by the mechanical stiffness signal and inactivated by metformin intervention may contribute to matrix stiffness-caused metformin resistance. Here, PTEN is linked to hepatocellular carcinoma.