Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant...Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

Importantly, the low mutation rate of TP53 in NPC suggests that BAY2402234 may be particularly effective in this cancer type. These findings provide the first comprehensive evidence that nucleic acid metabolism plays a crucial role in NPC progression and that the targeting of DHODH represents a promising therapeutic strategy, particularly via TP53-dependent mechanisms.

P=N/A, N=15, Active, not recruiting, University Hospital, Basel, Switzerland | Recruiting --> Active, not recruiting

P=N/A, N=100, Not yet recruiting, TC Erciyes University | Trial completion date: Jan 2027 --> Jun 2027 | Initiation date: Mar 2025 --> Nov 2025 | Trial primary completion date: Jan 2027 --> Jun 2027

These data support a significant role for a type II IFN-associated immune response in SjD pathogenesis, which is targeted by LEF/HCQ. Proteins associated with type II IFN-driven immune responses hold potential to monitor disease activity and predict treatment response.

P1, N=20, Not yet recruiting, The First Affiliated Hospital of Xinxiang Medical University; The First Affiliated Hospital of Xinxiang Medical University

P1, N=153, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

P=N/A, N=400, Recruiting, University Hospital, Montpellier | Trial completion date: Sep 2028 --> Jun 2030 | Trial primary completion date: Sep 2028 --> Jun 2030

P2, N=1, Terminated, Tata Memorial Centre | Practice changes, including leflunomide use for CMV, have led to a lack of musculoskeletal GVHD cases. Only one patient enrolled in the trial will continue treatment as per standard care.

P2, N=132, Recruiting, Peking University People's Hospital | Not yet recruiting --> Recruiting

P2, N=0, Withdrawn, Peking University People's Hospital | N=132 --> 0 | Recruiting --> Withdrawn

To overcome these limitations, we have engineered a calcium phosphate-mineralized ferroptosis inducer nanoplatform, termed Lf-PEG-CaP@iFSP1-Brequinar-Erastin-Fe3+-TA (LP-CaP@iBEFT), designed to augment ferroptosis by simultaneously targeting three key pathways: glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH). This approach effectively dismantles the "triple defense" mechanism that tumor cells employ to resist ferroptosis. In addition, this nanoplatform synergizes with anti-PD-L1 immune checkpoint blockade, enhancing the T cell-mediated destruction of tumor cells.