Colorectal cancer chemoprevention: Exploring the path from molecular mechanisms to available drugs

Colorectal cancer (CRC) remains a significant global health challenge despite advances in screening and diagnostic modalities that have contributed to reduced incidence and mortality. A substantial proportion of cases, however, continue to be diagnosed at advanced stages. Chemoprevention – the use of natural or synthetic substances to prevent cancer initiation or recurrence - has emerged as a promising strategy, particularly for individuals at elevated risk. While several agents have shown clinical efficacy, the underlying mechanisms driving their protective effects are not yet fully understood. In this Review, we provide a comprehensive overview of the molecular pathogenesis of CRC and highlight key druggable targets relevant to chemoprevention, including inflammation, polyamine metabolism, mitochondrial function, epigenetic regulation, and promising new avenues targeting aspects such as the tumor microenvironment and the gut microbiota. We provide a significant contribution to the field by intersecting the established clinical and preclinical results to the growing understanding of chemopreventative mechanism of action, identifying potential for the stratification of patient risks and benefits among their molecular roles and side effects. Finally, based on the improved molecular understanding of CRC tumorigenesis, we propose potential new avenues of colorectal chemoprevention.