SLC7A11, a plasma membrane protein, has been implicated as an oncogene in various cancers, including hepatocellular carcinoma (HCC). Its role in HCC pathogenesis, particularly in relation to ferroptosis, is not well understood. This study aims to investigate the function of SLC7A11 with ferroptosis and its interaction in development of HCC.Clinical HCC tissue samples were used to analyze the expression of SLC7A11 by RT-PCR. The impact of SLC7A11 on HCC cell viability, proliferation, and migration was assessed by CCK-8, AlamarBlue and Transwell. Protein-protein interactions were explored using co-immunoprecipitation and immunofluorescence. The effect of SLC7A11 on ferroptosis was evaluated by iron levels, ROS, and GSH. The impact of sorafenib and doxorubicin (DOX) on HCC cells was analyzed using cell viability assay.SLC7A11 was found to be highly expressed in HCC tissues and was correlated with tumor size and poor prognosis. Overexpression of SLC7A11 in HCC cells promoted cell viability, proliferation, and migration. Additionally, SLC7A11 overexpression mitigated erastin-induced ferroptosis, as evidenced by decreased ROS levels and increased GSH levels. We also discovered that SLC7A11 interacted with HSPB1. HSPB1 inhibited erastin-induced ferroptosis. Furthermore, a portion of the cell death induced by sorafenib and DOX is attributed to ferroptosis, with HSPB1 and SLC7A11 inhibiting the death induced by the two drugs, respectively.SLC7A11 plays a significant role in HCC progression by inhibiting ferroptosis, and its interaction with HSPB1 is a critical pathway in this process. Targeting the SLC7A11-HSPB1 axis may provide a novel therapeutic strategy for HCC treatment, highlighting the importance of understanding the mechanisms of ferroptosis in cancer cells.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.