IGF2BP3-NRF2 axis regulates ferroptosis in hepatocellular carcinoma

Poor sensitivity to sorafenib has been an important constraint on the efficacy of targeted therapy in advanced hepatocellular carcinoma (HCC). Therefore, it is particularly important to explore effective therapeutic targets to improve the sensitivity of HCC cells to sorafenib. Upregulation of IGF2BP3 is strongly associated with tumor invasion, early recurrence and poor prognosis in various human cancers, including HCC, but its roles in the sorafenib treatment of HCC remain unclear. In our study, IGF2BP3 knock-down significantly promoted ferroptosis in HCC cells through the evaluation of the Reactive Oxygen Species (ROS), Fe²⁺ and malondialdehyde (MDA) levels after sorafenib administration. In addition, NRF2 mRNA was identified as an important target of IGF2BP3 by bioinformatics analysis, RNA binding protein immunoprecipitation (RIP) and RNA pulldown experiments. More importantly, IGF2BP3, as an m6A (N6-Methyladenosine) reader, was shown to promote the stability of NRF2 mRNA by reading its m6A modification. Similar results were obtained from in vivo experiments. In summary, our study uncovered the role of IGF2BP3-NRF2 axis on ferroptosis in HCC, providing significant evidence for new anti-cancer strategies aimed at improving the efficacy of sorafenib.