circRNA‐SORE/UBQLN1/GPX4 Mediates the Acquisition of Sorafenib Resistance in Hepatocellular Carcinoma Through Inhibition of Ferroptosis

The clinical performance of targeted therapies for treating hepatocellular carcinoma (HCC) is significantly limited by the frequent emergence of drug resistance, ultimately resulting in therapeutic failure and poor prognosis. While the precise mechanisms underlying this resistance are not fully elucidated. Emerging evidence implicated that reactive oxygen species (ROS) homeostasis and ferroptosis, a unique form of programmed cell death, are closely associated with the development of drug resistance in cancer cells. In this study, we demonstrated that circRNA‐SORE, a circRNA previously reported by our group, played a crucial role in mediating sorafenib resistance via regulating intracellular ROS levels and inhibiting ferroptosis. Mechanically, we identified that circRNA‐SORE exerted its regulatory effects through modulating the level of UBQLN1. UBQLN1, via its STI domain, stabilized GPX4, a crucial antioxidant enzyme that protects against ferroptosis death. The stabilization of GPX4 promoted cancer cell survival under sorafenib‐induced oxidative stress. In conclusion, this study revealed a novel circRNA‐SORE/UBQLN1/GPX4 regulatory axis that mediated sorafenib resistance in HCC and also offered a promising therapeutic strategy to overcome drug resistance and improve clinical outcomes for patients with HCC.