Abstract

Breast cancer (BC) poses a persistent global health challenge, necessitating new therapeutic targets. The oncogenic translation factor Eukaryotic translation initiation factor 5A (eIF5A), while implicated in other cancers, lacks a mechanistic definition in BC. In this study, we found that eIF5A was significantly overexpressed in BC and correlated with poor clinical outcomes. Knocking down of eIF5A could suppress BC cell proliferation and migration in vitro, induce apoptosis and cell cycle arrest, and inhibit tumor growth in vivo in the MMTV-PyMT model. Mechanistically, eIF5A depletion induced mitochondrial dysfunction, characterized by elevated reactive oxygen species (ROS), reduced mitochondrial membrane potential (ΔΨm), compromised ATP synthesis and enhanced oxidative damage. These defects, along with the impaired tumorigenicity, were rescued by overexpressing the mitochondrial protease ATP-dependent Clp protease proteolytic subunit (ClpP). We further demonstrated that eIF5A promoted tumor progression, at least in part, by binding to and enhancing the translation of ClpP mRNA, leading to upregulation of ClpP. Importantly, we identified the eIF5A-ClpP axis as a key regulator of mitochondrial redox homeostasis in BC, and its disruption effectively suppressed malignant phenotypes. These findings established the eIF5A-ClpP axis as a mechanistically grounded and therapeutically targetable vulnerability for BC intervention.