Repurposing ribavirin for oncology: Integrating metabolism, signaling, and translational control.

Repurposing of approved drugs offers a rapid and cost-effective strategy for the identification of new therapeutic applications, particularly for difficult-to-treat and therapy-resistant cancers. Ribavirin, which is a synthetic guanosine analog and used as an antiviral drug, has demonstrated promising anticancer activity. To that end, the literature has presented varied anticancer mechanisms of action for ribavirin. This review integrates the current mechanistic evidence and proposes a working hypothesis in which ribavirin may influence interconnected metabolic, signaling, and translational processes that collectively induce its anticancer activity. Ribavirin inhibits inosine monophosphate dehydrogenase and depletes GTP, which may influence small GTPase-dependent signaling such as Ras-driven pathways. More recently, modulation of metabolic signaling by ribavirin has been proposed through the inhibition of AMP-activated protein kinase-associated pathways. These upstream perturbations may propagate through oncogenic signaling networks and complement the suppression of eukaryotic translation initiation factor 4E-dependent mRNA export and protein synthesis. Further, ribavirin treatment indirectly influences epigenetic regulators, inflammatory mediators, and immune checkpoint pathways, contributing to broader reprogramming of tumor cell behavior. Ultimately, ribavirin's effects lead to cell cycle arrest, apoptosis, and enhanced chemosensitivity across diverse cancer types. Taken together, the available evidence supports the hypothesis that ribavirin may function as a multilevel modulator of cellular growth networks, although the mechanistic relationships among these pathways remain incompletely defined. SIGNIFICANCE STATEMENT: This review theorizes ribavirin as a systems-level anticancer agent by integrating its effects on guanine nucleotide metabolism, oncogenic signaling, and eukaryotic translation initiation factor 4E-dependent translation into a unified metabolic-signaling-translation axis. In addition, it identifies the disparities in the mechanistic literature, which may assist in designing future studies.