DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target

Abstract

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.

Keywords: Cancer therapy; DHODH inhibitors; Dihydroorotate dehydrogenase (DHODH); Ferroptosis.

Fig. 1

The molecular mechanisms underlying ferroptosis and their interplay with cellular antioxidant defense systems Ferroptosis is fundamentally characterized by iron-dependent lipid peroxidation, which constitutes the core biochemical feature of this regulated cell death modality. The principal mechanisms driving ferroptosis involve the accumulation of redox-active iron and subsequent peroxidation of PUFAs in cellular membranes. This peroxidation cascade is initiated and propagated through various oxidative stress stimuli that overwhelm cellular antioxidant defenses. Multiple evolutionarily conserved antioxidant systems have been identified as critical regulators of ferroptosis, including the System Xc-GSH-GPX4 pathway, transsulfuration pathway, mevalonate pathway, FSP1-CoQ₁₀ pathway and DHODH-CoQH₂ pathway.

Fig. 2

The pyrimidine synthesis pathway The de novo pyrimidine biosynthesis pathway (indicated by red arrows) initiates with the CAD enzyme-catalyzed conversion of glutamine, bicarbonate, and aspartate into dihydroorotate. Subsequently, DHODH, located in the inner mitochondrial membrane, mediates the oxidation of dihydroorotate to orotate, which is further processed by the bifunctional UMPS enzyme to yield UMP. The process is accompanied by the production of CoQH₂, which can inhibit the generation of mitochondrial lipid peroxides, thereby resisting ferroptosis. In contrast, the pyrimidine salvage pathway (denoted by green arrows) utilizes extracellular uridine and cytidine, which are imported into cells via ENTs and CNTs. These nucleosides are then metabolized into UMP and CTP, respectively. Black arrows represent steps common to both pathways.

Fig. 3

The role of DHODH inhibitors in viral infection The quadruple mechanism of DHODH inhibitors encompasses (1) depletion of the pyrimidine nucleotide pool essential for viral replication, (2) activation of interferon-stimulated genes expression, (3) suppression of virus-induced cytokine storm, and (4) Disruption of the CoQ/CoQH2 redox cycle in mitochondria induces ferroptosis via lipid peroxide accumulation. Human cells acquire pyrimidines through two major pathways: de novo biosynthesis (red arrow) and the salvage pathway (green arrow).

Fig. 4

DHODH inhibitors regulate metabolism, endothelial function, and immune responses DHODH inhibitors attenuate FFA-induced lipid accumulation in hepatocytes by activating AMPK signaling and suppressing the DHODH pathway, which promotes eNOS phosphorylation to enhance NO production and improve endothelial function. Additionally, DHODH inhibition disrupts de novo pyrimidine synthesis, preventing T_Naive from differentiating into T_eff and reducing the release of inflammatory cytokines.