The study shows that mixing the chemotherapy drug epirubicin with radioactive iodine-125 seeds kills liver cancer cells better than either alone, and it does this by lowering levels of a protein called LL‑37, which then dampens a growth‑promoting WNT signaling pathway.

To investigate the role of iodine-125 (¹²⁵ I) combined with epirubicin (EPI) in inhibiting hepatocellular carcinoma (HCC) growth and promoting apoptosis. Both in vivo and in vitro experiments were conducted. CCK-8 assay was performed to determine the cells viability after EPI treatment. HepG2 and SMMC7721 cells were treated with EPI or ¹²⁵ I or in combination. Colony formation assays were performed to verify the antiproliferation effect. Annexin V-FITC/PI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, and western blotting were performed to analyze cellular apoptosis. Scratch wound healing assays and transwell assays were used to examine migration following different treatments. An isobaric tag for relative and absolute quantitation analysis was used to detect changes in protein expression after ¹²⁵ I treatment, identifying the potential mediating protein cathelicidin (LL-37). LL-37 protein and WNT pathway-related proteins were detected by western blotting in SMMC7721 and HepG2 cells. Mice were treated with ¹²⁵ I and EPI to evaluate whether EPI enhanced the antitumor effect of ¹²⁵ I. EPI promoted ¹²⁵ I-induced apoptosis and reduced the proliferation of HepG2 and SMMC7721 cells. EPI also prevented the migration of HepG2 and SMMC7721 cells. EPI combined with ¹²⁵ I may interfere with the WNT signaling pathway by decreasing LL-37 to inhibit HCC development. The antitumor effects of EPI with ¹²⁵ I were verified in mice. EPI combined with ¹²⁵ I induced apoptosis and inhibited the proliferation of HCC cells by LL-37 downregulating the WNT pathway.