Androgen receptor drives lenvatinib resistance in hepatocellular carcinoma through transcriptional activation of EIF3I and a downstream ceRNA axis

Lenvatinib resistance is a notable clinical challenge in advanced hepatocellular carcinoma (HCC). Androgen receptor (AR) upregulation has been associated with poor prognosis and high invasiveness, particularly in AR‑high HCC, yet its specific role in lenvatinib resistance remains unclear. The present study investigated whether AR confers resistance through regulating the circular RNA hsa_circ_0011385. Bioinformatic screening and experimental validation identified hsa_circ_0011385 as significantly upregulated in HCC tissues and AR‑high cell lines. In established lenvatinib‑resistant cells (MHCC97H‑LR), AR, hsa_circ_0011385 and Akt3 were upregulated, while miR‑212‑5p was downregulated. Mechanistically, AR directly bound to the promoter of eukaryotic translation initiation factor 3 subunit I (EIF3I), the host gene of hsa_circ_0011385 and promoted its transcription. The upregulated hsa_circ_0011385 acted as a molecular sponge for miR‑212‑5p, thereby relieving its inhibition of the downstream oncogene Akt3. Functional assays showed that AR knockdown sensitized resistant cells to lenvatinib, inhibiting proliferation and migration while promoting apoptosis, whereas overexpressing hsa_circ_0011385 reversed these effects. To the best of our knowledge, the present study revealed for the first time that in AR‑high HCC, AR drives lenvatinib resistance by activating the EIF3I/hsa_circ_0011385/miR‑212‑5p/Akt3 axis. This finding provides a new theoretical basis and potential therapeutic targets for overcoming lenvatinib resistance in this patient subset.