These results suggest that the knockdown of MDH2 enhances the susceptibility of HCC cells to RSL3-induced cell death through the upregulation of ROS, underscoring the critical role of MDH2 in preserving redox homeostasis and safeguarding HCC cells against oxidative stress and the cytotoxic effects induced by RSL3. This evidence concerns the gene MDH2 and hepatocellular carcinoma.