Abstract
Sorafenib, a first-line therapeutic option for advanced hepatocellular carcinoma (HCC), faces a formidable challenge in the form of emerging resistance. Recently, the oncogene DDX11 antisense RNA 1 (DDX11-AS1) has been implicated in various cancers, including HCC. However, its role in sorafenib resistance remains unknown. Our findings reveal that DDX11-AS1 is upregulated in sorafenib-resistant HCC cells, contributing to their resistance by suppressing ferroptosis. Further investigation elucidated the mechanism by which DDX11-AS1 activates the antioxidant Nrf2-Keap1 pathway. By interacting with Nrf2 and hindering its association with Keap1, DDX11-AS1 enhances the stability and nuclear translocation of Nrf2. In summary, our study unveils the potent role of DDX11-AS1 as an enhancer of sorafenib resistance, inhibiting sorafenib-induced ferroptosis through the activation of the Nrf2-Keap1 pathway in HCC. These findings offer a promising therapeutic strategy to overcome resistance and effectively treat HCC.