TABLE 4.

MYCN-associated metabolic pathways.

Metabolic pathway	Target/molecule	Mechanism	Intervention	Experimental model	Effects	Reference
Nucleotide Metabolism	GART	Aberrant purine metabolism in MYCN-amplified NB (MNA-NB)	Lometrexol (inhibitor)	MNA-NB cells	Induces differentiation and inhibits tumor progression	Jiang et al. (2025)
	DHODH	MYCN upregulates DHODH to promote pyrimidine synthesis	DHODH knock down or Brequinar, GSK983 (inhibitors)	Xenograft/transgenic mice	Delays tumor growth; combined with dipyridamole overcomes resistance	Yu et al., 2021b, Olsen et al., 2022
Lipid Metabolism	ELOVL2	MYCN recruits PRC1 to catalyze H2AK119ub and suppress ELOVL2	-	Multi-omics analysis	Reveals MYCN’s key role in lipid metabolism regulation	Ding et al. (2019)
	SLC27A2 (FATP2)	MYCN upregulates FATP2 to enhance fatty acid uptake	SLC27A2 inhibition	Mouse models	Blocks tumor growth	Tao et al. (2022)
	GLDC	MYCN transcriptionally regulates GLDC for glycine cleavage	GLDC knockdown	MNA-NB cells	Inhibits proliferation, induces G1 arrest, disrupts purine/lipid metabolism	Alptekin et al. (2019)
Amino Acid Metabolism	PHGDH	Rate-limiting enzyme for serine synthesis; higher demand in MNA-NB	PHGDH knockdown or NCT-503 (inhibitor)	MNA-NB cells and PDX models	Inhibits proliferation but may antagonize cisplatin	Arlt et al. (2021)
	MYCN-ATF4 feedback loop	MYCN and ATF4 form positive feedback to stabilize MYCN protein	-	MNA-NB cells	Counteracts FBXW7-mediated ubiquitination	Xia et al. (2019)
	Polyamine metabolism	MYCN elevates polyamines to suppress Let-7 miRNA	DFMO (inhibitor)	MNA-NB cell and TH-MYCN mice	Restores LIN28/Let-7 axis, inhibits tumor growth, induces G1 arrest	Powers et al., 2016, Koomoa et al., 2013
	ATP13A3	Mediates polyamine uptake and DFMO resistance	AMXT 1501 (combined with DFMO)	MNA-NB cells	Enhances polyamine depletion	Azfar et al. (2025)
	Arg/Pro restriction diet	Reduces ornithine to potentiate DFMO effects	Arg/Pro-free diet	TH-MYCN mice	Significantly extends survival	Cherkaoui et al. (2025)
Glucose Metabolism and Respiration	Glycolytic reprogramming	MYCN amplification induces glycolytic dependence	Overexpression of MYCN and 2-Deoxyglucose	NB cell lines	Suppresses glycolysis	Tjaden et al. (2020)
	Mitochondrial remodeling	MYCN alters mitochondrial network for energy adaptation	-	MNA-NB cells	Adapts to metabolic demands	Casinelli et al. (2016)
	MCT1-Complex I co-inhibition	MNA-NB sensitivity to MCT1 (AZD3965) and Complex I (phenformin) inhibition	AZD3965 + phenformin	MNA-NB cells	Disrupts glycolysis and ATP production	Dalton et al. (2021)
	Mitoribosomal inhibition	Doxycycline activates ISR to degrade N-Myc	Doxycycline	MNA-NB cells	Sustained proliferation inhibition without resistance	Borankova et al. (2023)
	Mitochondrial uncoupler	Niclosamide ethanolamine (NEN) disrupts mitochondrial metabolism	NEN (dietary supplement)	Orthotopic NB mice	Downregulates N-Myc and induces differentiation	Byrne and Bell 2023, Jiang et al., 2023
	ClpXP protease inhibition	ONC201 reduces mitochondrial membrane potential	ONC201	MNA-NB cells	Promotes neurite outgrowth and differentiation	Wu et al. (2023)
Ferroptosis	SELENOP-LRP8 axis	LRP8 protects MNA-NB by promoting selenocysteine synthesis	-	CRISPR screen	Confers ferroptosis resistance	Alborzinia et al. (2023)
	SCLY-SEPHS2-PRDX6 network	PRDX6 interacts with SEPHS2 for selenium delivery	-	MNA-NB subtype analysis	Associated with specific MNA-NB subtypes	Chen et al. (2024c)
	Glutathione metabolism	MNA-NB relies on cysteine metabolism to maintain GSH levels	BSO (inhibitor)	TH-MYCN mice	Delays tumor growth	Carter et al., 2016, Floros et al., 2021
	TfR1 (CD71) regulation	MYCN upregulates TfR1 to accumulate iron and increase ferroptosis sensitivity	Gambogic acid (GA)	MNA-NB cells/mice	Induces apoptosis via NK-IRE1-mTORC1 pathway	Lu et al., 2021, Bishayee et al., 2019
	Prognostic model	Ferroptosis-related target-based prediction model for MNA-NB	-	Clinical data analysis	Potential therapeutic target screening	Tan et al. (2025)