IDH1 Reprograms Nucleotide Metabolism by Inducing Chromatin Remodeling and DHODH Transcription to Drive Chemoresistance in Nasopharyngeal Carcinoma

Metabolic reprogramming under therapeutic stress may represent a targetable vulnerability for cancer treatment. Elucidation of the metabolic alterations linked to chemotherapy in nasopharyngeal carcinoma (NPC) could uncover potential therapeutic strategies. Using proteomics and transcriptomic profiles, we identified wild-type (WT) isocitrate dehydrogenase 1 (IDH1) as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin (GP) chemotherapy-resistant NPC. IDH1 reprogrammed nucleotide metabolism in response to chemotherapy, linking DNA damage repair (DDR) to ferroptosis resistance via dihydroorotate dehydrogenase (DHODH), thereby contributing to chemoresistance in NPC. Mechanistically, α-ketoglutarate (αKG), a metabolite of IDH1, enhanced chromatin accessibility to promote DHODH transcription via αKG-dependent dioxygenase AlkB homolog 5 (ALKBH5)-recruited heterogeneous nuclear ribonucleoprotein C (HNRNPC). The DHODH inhibitor BAY2402234 markedly sensitized NPC cells to chemotherapy. Clinically, a prognostic model based on DDR and ferroptosis signatures effectively predicted disease relapse risk following chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/αKG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring WT IDH1. SIGNIFICANCE: DHODH-mediated nucleotide metabolic reprogramming represents a targetable vulnerability to counteract chemoresistance in nasopharyngeal carcinoma with wild-type IDH1 overexpression.