Spermine Synthase at the Polyamine–Redox Interface: Mechanistic Evidence from Snyder–Robinson Syndrome and Cancer

Polyamines are essential metabolites whose biological effects depend on the balance among putrescine, spermidine, and spermine. Spermine synthase (SMS) catalyzes the terminal step of mammalian spermine biosynthesis, simultaneously consuming spermidine and producing spermine. We use this reaction as the organizing framework of the review: SMS changes redox biology indirectly by redistributing spermidine and spermine and by altering the substrate available for oxidative catabolism. In Snyder–Robinson syndrome (SRS), severe SMS deficiency causes spermine depletion, spermidine accumulation, oxidative and organelle stress, and multisystem disease. In cancer, SMS-dependent remodeling can support or restrain tumor growth according to the resulting polyamine profile and downstream metabolic context. Intact spermine can scavenge reactive species and chelate Fe2+, whereas SMOX- and SSAT–PAOX-mediated oxidation generates H2O2 and reactive aldehydes; these opposing routes help explain divergent effects on lipid peroxidation and ferroptosis. This review focuses on evidence that directly connects SMS perturbation or altered spermidine/spermine balance with redox-relevant outcomes in SRS and cancer, distinguishes causal studies from metabolite-level associations, and defines the present limits of therapeutic translation. Together, these findings identify the SMS–polyamine axis as a regulator of the balance between antioxidant protection and oxidase-driven oxidative stress.