Radiation therapy is among the most widely used treatments for lung cancer, but its effectiveness is frequently undermined by a familiar problem: Tumors that initially respond to treatment develop resistance and begin growing again. How exactly that resistance forms has remained incompletely understood, and the mechanisms that allow cancer cells to survive radiation-induced damage continue to be an active area of investigation.
A study published in Cancer Research from researchers at The University of Texas MD Anderson Cancer Center has now identified one key mechanism and a way to overcome it using a drug already approved by the FDA. The findings center on a mitochondrial enzyme called dihydroorotate dehydrogenase (DHODH) and its ability to protect lung cancer cells from ferroptosis, an iron-dependent form of cell death that radiation can trigger.
"This is an important finding because of the immediate translational opportunity," Boyi Gan, cancer biologist at UT MD Anderson, told DDN. "By understanding how DHODH is preventing cell death in radioresistant cancer cells, we were able to develop a strategy to overcome radiation therapy resistance in tumor models."
Two ways radiation kills
Radiation eliminates cancer cells through more than one mechanism. The better-known route is DNA damage: Radiation disrupts the genetic material inside a cell so severely that the cell can no longer repair itself, triggering apoptosis — a programmed cell death process that allows the body to safely clear damaged cells. But radiation also causes oxidative damage to cell membranes, and that membrane damage can trigger ferroptosis.
Ferroptosis, named for its dependence on iron-mediated lipid oxidation, has drawn increasing scientific attention as a cancer biology target because it operates through a pathway distinct from apoptosis. In the context of radiation therapy, the connection is particularly relevant: Radiation generates high levels of reactive oxygen species (ROS) that can initiate the lipid peroxidation cascade that drives ferroptotic cell death. That makes ferroptosis not a side effect of radiation, but a meaningful contributor to how it kills tumors.
"Ferroptosis is especially relevant to radiation therapy because radiation not only damages DNA but also generates high levels of oxidative stress in cancer cells," Gan told DDN. "We and others previously showed that this oxidative stress can trigger ferroptosis, making it an important way that radiation kills tumors."
But cancer cells adapt. Many tumor types activate protective mechanisms that suppress ferroptosis, allowing cells to survive the oxidative stress that radiation generates. "Many cancer cells adapt by activating protective pathways that suppress ferroptosis, allowing them to survive treatment," Gan said. "This means that blocking these defenses — and restoring ferroptosis — offers a promising way to overcome radioresistance and improve the effectiveness of radiation therapy."
Pointing to DHODH
The team set out to understand one of those mechanisms in radioresistant lung cancer cells.
"We took an unbiased approach to understand how cancer cells respond to radiation by analyzing their metabolism," Gan said. "This revealed that pyrimidine metabolism was strongly altered, and one enzyme involved in pyrimidine metabolism — DHODH — was consistently increased after radiation." When the team tested its function, they found that blocking DHODH, either genetically or with drugs, made lung cancer cells more sensitive to radiation.
DHODH is a mitochondrial enzyme that catalyzes a step in the biosynthesis of pyrimidines, the building blocks of RNA and DNA. Its upregulation after radiation makes functional sense from the cancer cell's perspective: More DHODH activity means more pyrimidine production, which supports the DNA repair the cell needs to survive radiation-induced damage. But the researchers found that DHODH contributes to radioresistance through a second mechanism that is distinct from DNA repair.
In addition to its role in pyrimidine synthesis, DHODH produces ubiquinol — a reduced form of coenzyme Q that functions as a lipid antioxidant — as a byproduct of its enzymatic activity. Ubiquinol, the researchers found, acts as a molecular brake on ferroptosis: By neutralizing lipid peroxides in the mitochondrial membrane, it prevents the oxidative cascade that would otherwise push radiation-stressed cells into ferroptotic death. In this way, DHODH serves as what the researchers called a metabolic shield, upregulated by radiation; it suppresses the very cell death pathway that radiation is trying to activate.
Leflunomide as a DHODH inhibitor
The clinical relevance of this finding depends substantially on what is available to inhibit DHODH. And here, the researchers had an important asset: leflunomide, an FDA-approved drug used to treat rheumatoid arthritis, is a known DHODH inhibitor whose safety profile, dosing, and side effects in patients are already well established.
Because leflunomide does not require the development timeline of a new compound — the preclinical toxicology, Phase 1 dose-escalation, and pharmacokinetic studies that a novel drug would need — its repurposing for radiation sensitization could significantly accelerate the path to clinical investigation. "Instead of starting from scratch, researchers can move more quickly into clinical trials that test how the drug works in combination with radiation and immunotherapy, bringing potential benefits to patients sooner,” said Gan. In preclinical testing, however, leflunomide alone produced only modest radiosensitization effects. The more striking results came from a triple combination that incorporated an additional biological axis.
The triple combination
When radiation was combined with immune checkpoint blockade — specifically anti-PD-1 therapy — the combination generated a biological effect that the researchers were able to exploit. Immunotherapy drives the activation of T cells, which release interferon-gamma (IFN-γ), a cytokine that independently promotes ferroptosis by suppressing the expression of genes that protect cells from lipid oxidation. IFN-γ and radiation thus push on the same ferroptotic pathway from different angles.
But in radioresistant cells, DHODH activity was sufficient to block ferroptosis even under the combined pressure of radiation and IFN-γ. When leflunomide was added to disable DHODH — removing the metabolic shield — the cells could no longer sustain their ferroptosis resistance, and tumors that had previously been refractory to treatment began to respond.
"DHODH inhibition alone had some effect on sensitization to radiation therapy, but it was really this triple combination that had a marked effect on the lung cancer models," Gan said. "These findings provide a good rationale for testing this combination in clinical studies."
The results were consistent across multiple lung cancer models, including different cell lines and both xenograft and immune-competent mouse models. "While leflunomide alone had only modest effects, the combination with radiation — and particularly with immunotherapy — led to strong tumor suppression and, in some cases, near elimination of radioresistant tumors," Gan said. The strategy could be broadly applicable rather than limited to a single tumor type, though more studies across a wider range of subtypes are still needed.
In the most responsive models, the triple combination produced near-elimination of radioresistant tumors — a result that leflunomide or radiation plus immunotherapy could not achieve on their own.
Ferroptosis and the broader resistance landscape
The DHODH–ferroptosis axis identified raises broader questions about how this pathway operates across cancer types and treatment modalities.
"While more studies are needed to determine how widely this pathway applies to other cancers or treatment resistance mechanisms, our findings provide a foundation for exploring its role beyond lung cancer and radiation therapy," Gan said. Cancer cells treated with certain chemotherapy drugs, targeted agents, and immunotherapies can also activate ferroptosis as a cell death mechanism, and the same protective pathways that enable radioresistance may contribute to resistance in those settings as well.
What the findings do establish is a mechanistic foundation for exploring this axis more broadly. DHODH as a target, ferroptosis as a vulnerability, and ubiquinol as the molecular intermediary connecting them — these components are all present in cancer biology beyond lung cancer and beyond radiation therapy.
For drug developers and translational researchers, the study's value lies partly in this broader potential and partly in the specificity of the mechanism it defines. Understanding that DHODH upregulation is an adaptive response to radiation, and not a pre-existing property of radioresistant cells, clarifies when and how inhibition should be applied. Plus, identifying ubiquinol as the mechanistic link between DHODH and ferroptosis resistance gives the field a molecular readout with which to assess DHODH activity and ferroptosis suppression in patient-derived samples.
