Abstract

Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.