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Academic Editor: Dooil Jeoung Received: 5 November 2025 Revised: 24 November 2025 Accepted: 26 November 2025 Published: 28 November 2025 Citation: Lee, J.; Roh, J.-L. Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy. Cells 2025, 14, 1889. https://doi.org/10.3390/ cells14231889 Show less

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders. Show less