Exosome-derived lnc-FAM72D-3 promotes lenvatinib resistance by remodeling hepatocellular carcinoma cytoskeleton via MBNL1/FAK axis.

Lenvatinib resistance (LR) profoundly exacerbates the prognosis of patients afflicted with advanced hepatocellular carcinoma (HCC). As pivotal mediators of intercellular communication, exosomes have been implicated in the development of LR. Nonetheless, the precise contributions of exosome-derived long non-coding RNAs (lncRNAs) to this phenomenon remain inadequately elucidated. Our prior investigations identified that lnc-FAM72D-3 is markedly up-regulated in the serum exosomes of HCC patients, yet its specific functions and underlying mechanisms remain only partially defined. In this study, we established lenvatinib-resistant HCC cell lines and organoids and demonstrated, through rigorous in vitro and in vivo experiments, that exosome-derived lnc-FAM72D-3 facilitates HCC progression and contributes to the phenomenon of LR. Mechanistically, lnc-FAM72D-3 augments the affinity of the E3 ubiquitin ligase HECTD3 for MBNL1, inciting lysine 48-linked ubiquitination and subsequent degradation of MBNL1. This degradation diminishes the interaction between MBNL1 and focal adhesion kinase (FAK), precipitating the de-nucleation of FAK and its activation by phosphorylation. The activated FAK subsequently reorganizes the cytoskeleton, markedly enhancing the proliferation, invasion, and stemness of HCC cells, thereby fostering LR. In summary, this investigation offers novel mechanistic insights into the regulatory role of exosomal lncRNAs in LR and posits a potential therapeutic strategy aimed at mitigating LR in patients with HCC.