摘要Telomere repeat binding factor 2(TRF2),a critical element of the shelterin complex,plays a vital role in the maintenance of genome integrity.TRF2 overexpression is found in a wide range of malignant cancers,whereas its down-regulation could cause cell death.Despite its potential role,the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown.Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis.Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits.Moreover,FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends,leading to the destruction of T-loop structure.Consequently,FKB04 promoted liver cancer cell senescence without modulating apoptosis levels.In corroboration with these findings,FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model,with no obvious side effects.These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2,showing promise in the treatment of liver cancer.