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

ABSTRACT:

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 IDH1 as a crucial metabolic enzyme upregulated in gemcitabine plus cisplatin chemotherapy (GP)-resistant NPC. IDH1 reprogrammed nucleotide metabolism in response to chemotherapy, linking DNA damage repair (DDR) to ferroptosis resistance via DHODH, thereby contributing to chemoresistance in NPC. Mechanistically, α-ketoglutarate (α-KG), a metabolite of IDH1, enhanced chromatin accessibility to promote DHODH transcription via α-KG-dependent dioxygenase ALKBH5-recruited 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 post-chemotherapy in NPC. This study links DDR to ferroptosis defense via the IDH1/α-KG/ALKBH5/DHODH axis, suggesting DHODH inhibition as a promising therapeutic strategy to overcome chemoresistance in tumors harboring wild-type IDH1.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11531 | MetaboLights | 2026-01-14

REPOSITORIES: MetaboLights

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	CTRL_DDP_1_T2327181a_N.wiff	Wiff
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	CTRL_DDP_2_T2327182a_N.wiff	Wiff
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	CTRL_DDP_3_T2327183a_N.wiff	Wiff

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