Therapeutic Targeting of miR-21 Restores SASH1 and Sensitizes HBV-HCC to Sorafenib

Background: Sorafenib resistance remains a major barrier to effective therapy in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Introduction: Here, we identified a previously undefined mechanism by which miR-21 promotes sorafenib resistance by suppressing the tumor suppressor SASH1 and enhancing HBx-driven PI3K/AKT/mTOR signaling. Methods: miR-21 expression was markedly elevated in HBV-HCC tissues, HBV-integrated HCC cell lines, and hypoxic conditions. Bioinformatic analyses and luciferase reporter assays confirmed SASH1 as a direct miR-21 target. Results: Mechanistically, SASH1 was functionally associated with HBx-related oncogenic signaling and influenced apoptotic responses. miR-21 inhibition reduced HBV-HCC cell proliferation, increased apoptosis, and restored sorafenib sensitivity in vitro. In an orthotopic HBV-HCC mouse model, the combined administration of miR-21 inhibitor and sorafenib elicited markedly greater tumor suppression and restoration of the SASH1 expression than either monotherapy did. Discussion: Therefore, these findings suggested that the miR-21/SASH1 pathway contributed to therapeutic resistance in HBV-associated HCC and highlighted that miR-21 targeting could be an efficient strategy to improve sorafenib response. Conclusions: The miR-21/SASH1 axis play a critical role in sorafenib resistance in HBV-associated HCC, and targeting miR-21 may provide a promising therapeutic strategy to enhance treatment efficacy.