Colorectal Precancerous Lesions: Molecular Mechanisms, Research Tools, and Natural Product‐Based Clinical Translation

ABSTRACT Colorectal cancer (CRC) is one of the most common and lethal cancers globally, with early detection of precancerous lesions being crucial for reducing its incidence and mortality. Colorectal precancerous lesions, including adenomas, serrated lesions, and dysplasias associated with inflammatory bowel disease (IBD), represent key targets for preventive strategies. Despite advancements in screening and therapeutic options, medicinal natural products clinical application is frequently challenged by low bioavailability, complex in vivo metabolism, unclear adverse effects and side‐effect profiles, and a strong reliance on empirical standards in clinical use. This review provides a comprehensive overview of the definition, classification, and molecular mechanisms underlying colorectal precancerous lesions, epigenetic modifications, and genetic factors. It also highlights the application of multi‐omics technologies in understanding lesion heterogeneity. In addition, the review evaluates cutting‐edge research models such as organoids, 3D co‐culture systems, and various in vivo models, offering insights into their potential for studying CRC precursors. This review summarizes current mechanistic insights into early colorectal carcinogenesis and highlights three major translational directions: therapeutic strategies targeting key genomic alterations; immunologic modulation relevant to inflammation‐driven tumor initiation; and multi‐omics stratification optimizing dosing and patient selection. These perspectives outline emerging opportunities for developing more precise and clinically actionable preventive interventions.