Targeting DNA damage: A natural product-based strategy for inhibiting cancer progression.

Ethnopharmacological relevance: DNA damage-induced genomic instability represents a fundamental hallmark of cancer progression. Natural products with multi-target and low toxicity characteristics can effectively utilize this mechanism for cancer treatment.

Aim of the study: This review aims to explore how traditional medicine derived natural products inhibit cancer progression by inducing DNA damage and clarify the multi-target mechanisms of action involved. It focuses on analyzing how natural products enhance the efficacy of chemotherapeutic drugs, reduce side effects, and overcome tumor drug resistance through oxidative stress, DNA repair inhibition, cell cycle arrest, and apoptotic signaling pathway activation.

Methods: To comprehensively assess the current research progress on natural products that inhibit cancer via DNA damage mechanisms, we performed a systematic retrieval and evaluation of both Chinese and English literature published from January 2000 to August 2025. Searches were conducted across major scientific databases, including PubMed, Elsevier, Springer, and CNKI (China National Knowledge Infrastructure), using keywords such as "DNA damage", "DNA fragment", "DNA fragmentation", "natural product", and "extract". In addition, we consulted classical texts and historical Chinese literature to explore the traditional uses of these natural products. All retrieved information was subsequently synthesized and critically analyzed.

Results: This review analyzed more than 200 articles and examined the research progress of over 80 active natural products that treat or synergistically enhance cancer therapy through inducing DNA damage. It provides a systematic overview of the sources, effects, and molecular mechanisms of these natural products, including alkaloids, flavonoids, terpenoids, glycosides, polysaccharides, and extracts, highlighting their roles in inducing oxidative stress in cancer cells, inhibiting DNA repair, regulating cell cycle checkpoints, and promoting apoptosis.

Conclusion: Natural products derived from traditional medicines can serve as dual-action agents, inducing both chemosensitization and cytotoxicity, through DNA damage-related pathways. This approach provides a promising strategy to overcome tumor drug resistance and advance precision oncology. Future research should prioritize exploiting synthetic lethal effects, optimizing drug delivery systems, and improving clinical applicability through emerging technologies such as PROTAC.