Mechanisms and Therapeutic Advances of Natural Products Regulating Non-Coding RNAs in Cancer

Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, tRNA-derived fragments, PIWI-interacting RNAs, and small nucleolar RNAs, have been identified as crucial regulators of gene expression and key drivers of cancer progression. Natural products, owing to their structural diversity and multi-targeting capacity, represent a promising reservoir for anticancer drug discovery through the modulation of these ncRNA networks. This review provides a comprehensive overview of the regulatory roles of natural products on ncRNAs in cancer. Compared with previous reviews that focus on individual ncRNA classes or single natural product categories, this review provides an integrated framework linking ncRNA biology, natural product pharmacology, and therapeutic delivery in cancer. First, the biogenesis, classification, and molecular functions of major ncRNA classes are systematically described, and the dysregulation of each ncRNA class across various cancer types and their contributions to tumor pathogenesis are then discussed. Subsequently, the modulation of these ncRNA networks by representative natural products, including polyphenols, flavonoids, terpenoids, and alkaloids, to influence multiple hallmarks of tumor progression, encompassing cell proliferation, programmed cell death, metastatic dissemination, tumor microenvironment remodeling, and therapeutic resistance, is reviewed. The potential of ncRNAs as diagnostic, prognostic, and pharmacodynamic biomarkers in the context of natural product-based therapy is discussed, together with emerging nanoparticle-based delivery strategies for co-delivering natural products and ncRNA therapeutics; however, most of the evidence summarized here remains preclinical, and clinical translation will require rigorous pharmacological and clinical validation. Finally, we address current challenges and future perspectives for the clinical translation of natural product–ncRNA-based anticancer strategies.