DHODH-Mediated Suppression of Ferroptosis Supports Radioresistance and Represents a Therapeutic Vulnerability in Lung Cancer

Radiotherapy (RT) is a mainstay in the treatment of solid tumors, including lung cancer, yet the long-term efficacy is often limited by radioresistance. RT promotes multiple different cell death processes, and gaining mechanistic insights into how metabolic cell death pathways like ferroptosis contribute to resistance could enable the development of effective modulators of radiation sensitivity. Here, through metabolomic and functional analyses, we identified dihydroorotate dehydrogenase (DHODH) as a critical regulator of radioresistance in lung cancer. DHODH expression was induced by radiation in a CREB-dependent manner, and both radiation exposure and acquired radioresistant states were associated with elevated DHODH activity. DHODH promoted radioresistance in part by generating ubiquinol, a mitochondrial lipid antioxidant that suppresses ferroptosis, and by supporting DNA repair through its role in de novo pyrimidine synthesis. While DHODH inhibition alone had limited therapeutic effect, its combination with IFN-γ (delivered directly or via anti-PD-1 immunotherapy) synergistically enhanced RT-induced ferroptosis and overcame radioresistance in preclinical models. These findings reveal a metabolic mechanism of radioresistance driven by DHODH-mediated ferroptosis defense and provide a rationale for combining DHODH inhibitors with RT and immunotherapy in lung cancer and potentially other solid tumors.