Preclinical findings suggest that targeting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) can restore ferroptosis-driven cell death, pointing to new therapeutic strategies that may be used to induce ferroptosis and inhibit tumor growth.

Ferroptosis is a form of controlled cell death triggered by the toxic accumulation of lipid peroxides in the cell. Because lipid peroxides are generated through normal metabolic activities, cells also have mechanisms in place to defend against ferroptosis. Glutathione peroxidase 4 (GPX4) is one of the key defense mechanisms identified to date. 

In this study, the researchers used GPX4 inhibitors to block its activity and to identify new defense mechanisms. Metabolic analyses pointed them to DHODH, a mitochondrial enzyme that normally is involved in the pyrimidine biosynthesis pathway.

In cells with low GPX4 expression, loss of DHODH activity led to the accumulation of lipid peroxides in mitochondria and the activation of ferroptosis. By contrast, cells with high GPX4 expression were able to continue blocking ferroptosis activity in the absence of DHODH. The findings suggest that DHODH and GPX4 work as redundant defense mechanisms in the mitochondria to prevent ferroptosis.

The researchers further clarified DHODH's role in regulating ferroptosis and then investigated the therapeutic potential of targeting this enzyme in cancer cells. Using extensive preclinical models, they evaluated the DHODH inhibitor brequinar, which has been tested in multiple clinical trials for other indications.

In GPX4-low cancers, brequinar effectively induced ferroptosis and suppressed tumor growth, but the effects were not seen in GPX4-high cancers. However, the combination of brequinar and sulfasalazine, an FDA-approved ferroptosis inducer, resulted in a synergistic effect to overcome high GPX4 expression and to block tumor growth.