Abstract

Cancer remains a leading global health challenge, with treatment efficacy often limited by resistance to conventional therapies and their associated toxicities. These limitations have intensified the exploration of alternative strategies, particularly natural compounds with antitumor potential such as Artemisia annua (AA). The objective of this review was to systematically evaluate the antitumor efficacy and mechanisms of AA extracts and derivatives in preclinical animal models. A structured literature search was conducted in PubMed, Scopus, and Web of Science for studies published between 2019 and August 2025, following PRISMA 2020 guidelines with the protocol prospectively registered in PROSPERO (CRD420251113840). Eligible articles were original in vivo investigations reporting the anticancer activity of AA or its derivatives. From 176 records initially identified, 21 underwent full-text review, and seven studies met the inclusion criteria for synthesis. Across these studies, six (86%) reported measurable reductions in tumour size or volume, and four documented apoptosis induction. Additional mechanisms included inhibition of angiogenesis and activation of ferroptosis. The most frequently investigated derivative was dihydroartemisinin (DHA), while novel compounds such as ZQJ29 also showed promising activity. Importantly, systemic toxicity was reported as minimal in most studies, supporting a favourable safety profile. This review is the first to consolidate recent preclinical evidence highlighting ferroptosis as a key mechanism of AA derivatives, thereby expanding the understanding of their multifaceted anticancer activity. Collectively, the findings underscore the therapeutic promise of AA derivatives and advocate for further investigation into their pharmacokinetics, safety, and integration into combination regimens with established therapies. These results demonstrate that AA compounds hold significant potential as adjuncts or alternatives in cancer management and warrant rigorous evaluation in standardized clinical trials.

Key words: Angiogenesis; Apoptosis; Artemisia annua; Cancer therapy; Ferroptosis.