Small molecule as potent hepatocellular carcinoma progression inhibitor through stabilizing G-quadruplex DNA to activate replication stress responded DNA damage.

G-quadruplex (G4) DNA, prevalent in tumor cells, offers a potential anticancer target. This study examined TA-1, a tanshinone IIA derivative, for its antitumor activity against liver cancer. We found that TA-1 binds and stabilizes multiple G4 DNA,triggering DNA damage, suppressing the angiogenesis in vitro and in vivo and leading to cancer cell death. Notably, we confirmed TA-1's inhibitory effect on liver cancer cells and explored its mechanism, which involves stabilizing G4 DNA to mediate replication-stress-dependent DNA damage. Furthermore, TA-1 promotes 53BP1 expression, activating toxic NHEJ repair and leading to apoptotic cell death via the ATM-Chk2-p53 pathway. In vivo studies further supported these findings. In summary, TA-1 is a potent VEGF G-quadruplex stabilizer that inhibits liver cancer progression.