SHC4 suppresses ferroptosis and promotes sorafenib resistance in hepatocellular carcinoma by disrupting the interaction between NCOA4 and FTH1

Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in hepatocellular carcinoma (HCC) progression and is now recognized as a key mechanism underlying the antitumor activity of sorafenib. Src homology and Collagen protein 4 (SHC4), an adaptor protein implicated in oncogenic signaling and tumor progression, has recently emerged as a potential regulator in multiple cancers; however, its involvement in Ferroptosis and sorafenib response remains unclear. Our preliminary data showed that sorafenib treatment alters SHC4 expression in both clinical tissues and HCC cell models, suggesting a possible connection between SHC4 and ferroptotic susceptibility. These findings prompted us to investigate whether SHC4 modulates Ferroptosis and contributes to sorafenib resistance. Here, we found that SHC4 decreased the anti-tumor activity of sorafenib by reducing Ferroptosis both in vitro and in vivo. SHC4 diminished ROS and MDA production, lowered intracellular iron levels, enhanced GSH levels, and regulated the expression of Nrf2, xCT, and GPX4 proteins associated with antioxidant stress. In addition, SHC4 interacts with the 383-522 fragment of NCOA4, thereby blocking the association between NCOA4 and FTH1. This interference reduces the lysosomal degradation of FTH1, leading to decreased intracellular Fe²⁺ levels and ultimately suppressing Ferroptosis. Clinically, the concurrent overexpression of SHC4 and FTH1 has been identified as a potential prognostic marker for poor outcomes in patients with hepatocellular carcinoma. Collectively, our study demonstrates the pivotal role of SHC4 in regulating Ferroptosis in hepatocellular carcinoma and highlights its potential as a novel therapeutic target for overcoming sorafenib resistance.