Spermidine in Colorectal cancer: friend or foe?

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related mortality, and its incidence is rising among individuals, especially young, underscoring the need for novel therapeutic strategies. CRC development is driven by genetic and epigenetic alterations in key oncogenic pathways and is accompanied by profound reprogramming of polyamine metabolism. In this context, spermidine (SPD), a central polyamine produced downstream of the MYC–ODC axis, is regarded as a pro-tumorigenic metabolite that sustains CRC growth by fueling eIF5A hypusination and MYC translation, thereby establishing a feed-forward MYC–ODC–polyamine–eIF5A circuit that promotes tumorigenesis. Recent studies also show that combined inhibition of polyamine biosynthesis and eIF5A hypusination synergistically impairs MYC translation and suppresses CRC growth in preclinical models, outperforming single-agent strategies such as ornithine decarboxylase (ODC) blockade with difluoromethylornithine (DFMO) and highlighting the translational potential of dual targeting of this axis. Conversely, other lines of evidence indicate that excessive SPD or altered flux through the polyamine pathway can be cytotoxic: multiple reports demonstrate that high-dose SPD triggers apoptosis, while experimental models suggest that SPD and epithelial eIF5A hypusination can protect against colitis and colitis-associated cancer by supporting the translation of detoxifying enzymes. Overall, the literature points to a dual role of SPD, and the aim of this review is to dissect the functions of SPD in CRC, to summarize and critically discuss the potential benefits of this polyamine, and to evaluate how it might be rationally exploited as a therapeutic agent in cancer.