Res Sq. 2025 Nov 05. pii: rs.3.rs-7906468. [Epub ahead of print]
Alain P Gobert,
Kara M McNamara,
Caroline V Hawkins,
Mohammad Asim,
Daniel P Barry,
Alberto G Delgado,
Kristie L Rose,
Purvi Patel,
Regina N Tyree,
Kate S Carson,
Lori A Coburn,
M Blanca Piazuelo,
Keith T Wilson.
Hypusine is a unique amino acid synthesized on the eukaryotic initiation factor 5A (EIF5A) from the polyamine spermidine by deoxyhypusine synthase (DHPS). Hypusination of EIF5A plays a key role in translation. Here, we examined the contribution of the epithelial hypusination pathway to gastric inflammation induced by Helicobacter pylori . Immunohistochemical analyses revealed increased expression of DHPS and hypusinated EIF5A (EIF5A Hyp ) in the gastric mucosa of patients with H. pylori gastritis compared to uninfected individuals, notably within gastric epithelial cells (GECs) and immune infiltrates. Then, we created a mouse model with epithelial-specific deletion of Dhps ( Dhps Δepi ) and confirmed the reduction of DHPS and EIF5A Hyp in GECs. H. pylori -infected Dhps Δepi mice exhibited an attenuation of gastric histologic inflammation scores compared with infected Dhps fl/+ controls, without alteration in bacterial colonization levels. Quantitative proteomics of isolated GECs showed that Dhps deletion altered the expression of proteins involved in organismal injury, cancer, and gastrointestinal diseases in naïve mice. Upon H. pylori infection, inflammatory and immune response proteins, including signaling factors and immunoglobulin mediators, were less induced in Dhps Δepi GECs, and pathways linked to tissue injury and inflammation were selectively downregulated. Together, these findings demonstrate that epithelial hypusination supports H. pylori -driven gastric inflammation without affecting bacterial persistence. Targeting DHPS-dependent EIF5A hypusination may thus represent a novel therapeutic strategy to limit H. pylori -associated mucosal injury and disease progression.