Multi-cohort analysis and experimental study on the function of squalene epoxidase as a ferroptosis inhibitor in HCC

Squalene epoxidase (SQLE) drives hepatocellular carcinoma (HCC) development via increased hepatic oxidative stress, a hallmark of ferroptosis. Although investigations have progressed, the precise link between SQLE and ferroptosis in HCC remains indistinct. In this study, multi-omics data were employed to identify ferroptosis-associated genes linked to SQLE in HCC, which were subsequently categorised into two prognostic risk categories. Kaplan-Meier analysis revealed patients allocated to the high-risk group exhibiting markedly poorer outcomes compared to those in the low-risk group, thereby underscoring the independent prognostic value of the ferroptosis-related prognostic signature in HCC. Furthermore, MTT assays further demonstrated that overexpression of SQLE conferred resistance to the ferroptosis inhibitor Fer-1 in cancer cells, while reduced expression of SQLE augmented cellular susceptibility to ferroptosis. Additionally, the expression levels of SQLE were found to positively correlate with the ferroptosis inhibitor gene PARP2. Knockdown of PARP2 significantly mitigated SQLE-induced cholesterol accumulation and cellular proliferation. This study illustrates the role of SQLE as a ferroptosis inhibitor in HCC, offering novel insights into the prognostic evaluation and molecular mechanisms underlying HCC.