DHODH (Dihydroorotate Dehydrogenase (Quinone))

Beclin1 knockdown and DHODH overexpression can reduce DOX-induced liver injury by preventing ferroptosis and autophagy.

BAY-2402234, a DHODH inhibitor, effectively kills pS6+ cells in vitro, with IC50 values correlating with pS6 signaling strength across 14 B-ALL patient-derived xenografts (PDX). In vivo, DHODH inhibition prolongs survival and reduces leukemia burden in pS6+ B-ALL models. These findings link active signaling to pyrimidine dependency and relapse risk, highlighting DHODH inhibition as a promising therapeutic strategy for chemo-resistant B-ALL.

This targeted intervention disrupted the binding of YY1 to DHODH promoter G4, potently suppressed DHODH expression, and significantly sensitized melanoma cells to ferroptosis inducers. Our work uncovers a non-canonical, activating function of a promoter G4 structure in driving pro-tumorigenic gene expression and provides a precise therapeutic strategy for sensitizing tumors to ferroptosis by targeting transcriptional regulation.

Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors.

Pharmacological co-targeting of PDE7A and DHODH potently inhibits TNBC tumor growth and metastasis. These findings identify the PDE7A → DHODH →de novo pyrimidine biosynthesis pathway as a key driver of TNBC, offering additional therapeutic opportunities for TNBC patients.

These findings suggest that CIRT promotes ferroptosis and drives M1-like macrophage polarization through DHODH suppression. Targeting DHODH may enhance the therapeutic efficacy of CIRT in gastric cancer.

Additionally, flubendazole enhanced the sensitivity of cervical cancer cells to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition and showed a potent synergistic anti-tumor effect in combination with GPX4 inhibitor in xenograft mouse models. These findings highlight the promising potential of flubendazole as a repurposed drug for cervical cancer therapy by inducing ferroptosis through inhibition of DHODH.

High expression of DHODH and NRP1 in human breast and lung cancer tissues predicted patients' poor prognosis. Therefore, targeting DHODH to inhibit tumor cell macropinocytosis provides a potential approach to reverse immunosuppression for improving cancer immunotherapy.

These findings demonstrate the relevance of metabolic profiling and scoring in the design of therapeutic approaches targeting the bioenergetic vulnerabilities of tumors and suggest DHODH as a promising therapeutic target in the low-metabolic score subgroup of cSCC.

These findings link active signaling to uridine dependency in B-ALL cells and an associated risk of relapse. Targeting uridine synthesis through DHODH inhibition offers a promising therapeutic strategy for chemo-resistant B-ALL as a novel therapeutic approach for resistant disease.

LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.

We showed that MCF-7 and MDAMB-231 cells of the subtypes (ER+/PR+/HER2-) and (ER-/PR-/HER2-), respectively, were responsive to brequinar...Collectively, we have found that MDAMB-231 TNBC cell was the most affected by DHODH inhibition in terms of sensitivity, cell cycle arrest, induction of cell differentiation, production of ROS, and mitochondrial complexes disruption. In conclusion, these findings suggest that DHODH inhibitors can potentially become a valuable targeted therapy for TNBC subtype and further consolidates its therapeutic potential as part of the combinatorial therapy against this resilient breast cancer subtype.