The knockdown of MDH2 decreased the GPX4 protein level by impeding its protein stability, and MDH2 knockdown-mediated sensitization of HCC cells to RSL3-induced ferroptosis was rescued by overexpression of GPX4, suggesting that MDH2 regulates the HCC ferroptosis pathway mainly via the regulation of GPX4. This evidence concerns the gene GPX4 and hepatocellular carcinoma.