In this study, our findings, for the first time, demonstrate that TFPI2 exerts a crucial role in the CCAR2-GADD45A-inducing DNA damage pathway, bringing groundbreaking new insights for alleviating the challenges posed by the development of HCC and chemotherapy resistance, heralding a new era of precision medicine and personalized therapeutic strategies. The gene discussed is CCAR2; the disease is hepatocellular carcinoma.