<p>Metabolic reprogramming and genome instability represent two fundamental hallmarks of cancer. Emerging studies now demonstrate that specific metabolic alterations directly fuel replication stress, DNA damage, and compromised DNA damage response. This underscores that metabolites are not merely passive by-products but active biochemical regulators of genome instability. Perturbation of specific metabolic pathways can preferentially unmask these vulnerabilities for therapeutic targeting. In this review, we propose an integrated framework highlighting metabolism-induced genome instability as a potential therapeutic target. By delineating the metabolic targets that induce genome instability, we provide a comprehensive overview of the complex interplay between metabolic pathways and genome stability. We further highlight that metabolism-induced genome instability can be strategically exploited to potentiate standard-of-care therapies. Collectively, these insights redefine metabolism-induced genome instability as a targetable vulnerability of cancer. This systematic synthesis provides a mechanistic rationale for next-generation therapeutic designs in which metabolic interventions are leveraged to convert genome instability into actionable clinical vulnerabilities.</p>