FGF19/FGFR4/KLB signaling participate in the ferroptosis regulation of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the main histopathological type of liver cancer and the fourth major cause of cancer-related mortality globally, yet the treatment options are very limited. Ferroptosis is a unique iron-dependent form of oxidative cell death process that plays essential regulatory roles in the occurrence and development of HCC. However, the underlying mechanism in ferroptosis regulation in HCC remains inadequately understood. Aberrant activation of fibroblast growth factor 19-fibroblast growth factor receptor 4-βKlotho (FGF19-FGFR4-KLB) signaling is considered carcinogenic driving pathway in patients with HCC. Recently, increasing evidence has shown that FGFR4 inhibition could trigger ferroptosis process in many tumors. However, as an important ligand of FGFR4, the role of FGF19 in the regulation of ferroptosis remains unclear. In this research, results of western blotting and reactive oxygen species (ROS) assay demonstrated that knock down of KLB enhance the expression of TFRC, a driver gene of ferroptosis, thus blocking the ferroptosis inhibitory effect of FGF19. Based on these available evidence and data, we hypothesize that FGF19 signaling inhibit the ferroptotic cell death in HCC cells through FGFR4-KLB co-receptors, while suppression of FGFR4-KLB could block FGF19 signaling, thus trigger ferroptosis process.