BBOX1-AS1 mediates Lenvatinib resistance through IGF2BP1-dependent MYC mRNA stabilization

Lenvatinib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC); however, acquired lenvatinib resistance remains a major challenge. Here, we identify BBOX1-AS1 as a new mediator of lenvatinib resistance in HCC. BBOX1-AS1 is markedly upregulated in lenvatinib-resistant HCC cell lines and in tumor specimens from patients who progressed during lenvatinib treatment. Lower BBOX1-AS1 expression was associated with significantly longer progression-free survival (median PFS, 8 vs 3.7 months; P = 0.0041). Furthermore, knockdown of BBOX1-AS1 restored lenvatinib sensitivity in both cell and xenograft models. Mechanistically, BBOX1-AS1 binds the RNA-binding protein IGF2BP1 and promotes its recruitment to MYC mRNA, stabilizing the transcript, elevating c-Myc protein, and activating AKT signaling. Actinomycin D chase assays and IGF2BP1 knockdown experiments further established that BBOX1-AS1-mediated MYC mRNA stabilization is dependent on IGF2BP1. These findings indicate that the BBOX1-AS1/IGF2BP1/c-Myc axis contributes to lenvatinib resistance in HCC. BBOX1-AS1 may serve as a biomarker for lenvatinib response and a potential therapeutic target in resistant HCC.