SCARA5 deficiency inhibits ferroptosis via regulating iron homeostasis and results in sorafenib resistance in hepatocellular carcinoma

SCARA5 (Scavenger Receptor Class A Member 5), a member of scavenger receptor class A, is a type II transmembrane protein. Previous studies, including our own, have suggested that SCARA5 acts as a tumor suppressor in various cancers. Additionally, SCARA5 has been identified as a ferritin receptor that facilitates iron delivery independent of transferrin. However, it remains unclear whether ferroptosis is involved in the tumor-suppressive function of SCARA5 in hepatocellular carcinoma (HCC). In this study, we found that SCARA5-deficient cells, including mouse embryonic fibroblasts (MEFs) and HCC cells, exhibited reduced sensitivity to ferroptosis induced by erastin and RSL3. We measured the cell viability, cellular reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA) and ferrous iron concentration to assess the role of SCARA5 in ferroptosis. Mechanistically, we confirmed that SCARA5 might enhance the intracellular availability of bioactive ferrous iron by promoting autophagic degradation of the major iron storage protein ferritin. Furthermore, we found that SCARA5 deficiency contributed to the resistance of HCC cells to sorafenib, a therapeutic agent for HCC, possibly by inhibiting ferroptosis. Collectively, our study revealed the role of SCARA5 in regulating ferroptosis, providing a profound understanding of sorafenib resistance in HCC systemic therapy.