The hypusine circuit: eIF5A at the crossroads of polyamine metabolism, malignant progression, and therapeutic vulnerability.

Hypusination of eukaryotic translation initiation factor 5 A (eIF5A) is a highly conserved post-translational modification. This process uniquely depends on spermidine and is catalyzed sequentially by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Recent studies have established eIF5A hypusination as a key translational regulatory mechanism linking polyamine metabolism to tumor progression. By relieving ribosomal stalling in selected difficult-to-translate targets, hypusinated eIF5A directly controls defined translational outputs. Through these direct mechanisms, as well as broader downstream signaling and phenotypic effects whose immediate translational targets remain incompletely resolved, the hypusination pathway has been linked to tumor cell proliferation, invasion and metastasis, angiogenesis, therapeutic resistance, and adaptive stress responses. This review critically distinguishes sequence-resolved translational mechanisms from target-level regulatory associations and indirect phenotypic consequences through which eIF5A hypusination is linked to these cancer hallmarks and further examines pharmacological and genetic strategies targeting the polyamine-eIF5A axis, including inhibitors of polyamine metabolism, DHPS, and DOHH. It also discusses the potential translational significance of these strategies in cancer therapy. Overall, eIF5A hypusination may act as a central effector that converts metabolic inputs into oncogenic protein outputs and represents a promising therapeutic target across diverse tumor types.