Table 1.

Polyamine metabolic vulnerabilities in cancer and other diseases.

Interacting Metabolic Pathway	Deregulated Enzymes/Genes	Target (Inhibitor)	Target Polyamine (Inhibitor/Compound)	Description	Disease	Ref.
Arginine pathway	ASS1	Arg depletion (ADI-PEG20)	ODC inhibition (DFMO)	ASS1-deficient cells have decreased levels of acetylated polyamines along with compensatory increases in polyamine biosynthetic enzymes.	Malignant pleural mesothelioma (MPM)	[130]
Arginine pathway/Urea cycle	ARG2	N/A	Polyamine toxicity	ARG2 suppresses tumor growth via depletion of biosynthetic cofactor PLP and toxic polyamine accumulation.	Clear cell renal cell carcinoma (ccRCC)	[131]
Urea cycle	p53 repressive target genes; CPS1, OTC and ARG1	N/A	ODC translation	p53-induced ammonia accumulation represses ODC translation.	Colon cancer	[63]
Arginine pathway/Urea cycle	ARG1	Inhibition of arginase (nor-NOHA)	ODC (DFMO)	Increased polyamine production in PP6-deficient keratinocytes facilitates self-RNA sensing by dendritic cells in psoriasis.	Psoriasis	[132]
Cysteine metabolism		Cysteine starvation	MTAP deletion	MTAP deletion upregulates polyamine pathway, which promotes ferroptosis under cysteine starvation.	Colorectal, breast and pancreatic cancers, and glioblastoma	[119]
Methionine salvage pathway		MTAP inhibition (MTDIA)	SSAT activation (BENSpm)	While keeping the high polyamines flux, SAM pools are depleted by inhibition of methionine salvage pathway.	Prostate cancers	[115]