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. Here, MDH2 is linked to hepatocellular carcinoma.