Study reveals mitochondrial enzyme plays a vital role in preventing ferroptosis

According to a recent study published in Nature by researchers at The University of Texas MD Anderson Cancer Center, the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) plays a significant and previously unknown function in preventing a form of cell death called ferroptosis.

Boyi Gan, PhD. Image Credit: The University of Texas MD Anderson Cancer Center.

Preclinical evidence suggests that targeting DHODH can restore ferroptosis-driven cell death, leading to potential therapeutic strategies for inducing ferroptosis and inhibiting tumor development.

By understanding ferroptosis and how cells defend against it, we can develop therapeutic strategies to block those defense mechanisms and trigger cell death. We have discovered that DHODH plays a key role in defending against ferroptosis and shown that we can exploit this vulnerability with clinically tested therapies.”

Boyi Gan, PhD, Study Senior Author and Associate Professor, Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center

Ferroptosis is a newly discovered form of regulated cell death caused by a toxic buildup of lipid peroxides in the cell. Since lipid peroxides are produced during normal metabolic processes, cells have mechanisms in place to protect themselves from ferroptosis. Glutathione peroxidase 4 (GPX4) is one of the most important defense mechanisms discovered to date.

The researchers used GPX4 inhibitors to suppress its function and establish new defense mechanisms in this research. DHODH, a mitochondrial enzyme usually involved in the pyrimidine biosynthesis pathway, was identified by metabolic analysis.

Loss of DHODH function in cells with low GPX4 expression resulted in the aggregation of lipid peroxides in mitochondria and the triggering of ferroptosis. Cells with high GPX4 expression, on the other hand, were able to continue suppressing ferroptosis activity in the absence of DHODH.

According to the results, GPX4 and DHODH function as redundant defense mechanisms in the mitochondria to avoid ferroptosis.

The researchers explored the therapeutic potential of targeting DHODH in cancer cells after further clarifying DHODH’s function in controlling ferroptosis. They examined the DHODH receptor brequinar, which has been investigated in several clinical trials for other indications, using extensive preclinical models.

Brequinar successfully caused ferroptosis and inhibited tumor development in GPX4-low cancers, but not in GPX4-high cancers. The combination of sulfasalazine and brequinar, an FDA-approved ferroptosis inducer, had a synergistic effect in overcoming high GPX4 expression and inhibiting tumor development.

We were able to leverage our understanding of a new ferroptosis defense mechanism into a novel therapeutic strategy that appears promising in preclinical studies. Because ferroptosis is active across cancer types, we believe this could have broad implications, particularly in cancers with low expression of GPX4.”

Boyi Gan, PhD, Study Senior Author and Associate Professor, Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center