Natural products against Babesiosis: active compounds, molecular mechanisms, application limitations and...

Babesiosis is an important tick-borne disease affecting humans and a wide range of domestic and wild animals, with substantial implications for public health, animal welfare, and livestock production. Despite the increasing global burden of babesiosis, currently available therapeutic options are limited by variable efficacy, drug resistance, adverse effects, and, in veterinary settings, concerns regarding drug residues. Natural products have emerged as an important source of antiparasitic agents owing to their remarkable chemical diversity, multi-target activities, and broad pharmacological potential. In this review, we comprehensively summarize the current knowledge on natural products with antibabesial activity, with emphasis on their major classes, representative compounds, proposed molecular mechanisms, and translational prospects, while distinguishing evidence derived from in vitro assays, animal studies, and the still very limited clinical investigations. Available evidence indicates that diverse natural products exhibit inhibitory activity against Babesia spp. predominantly in vitro, whereas only a smaller number have shown efficacy in animal models and clinical evidence remains scarce. These products appear to act through multiple mechanisms, such as disruption of redox balance, mitochondrial dysfunction, interference with nucleic acid biosynthesis, and suppression of energy metabolism and parasite proliferation. Although the development of natural products for babesiosis control remains hindered by insufficient mechanistic validation, limited in vivo and clinical evidence, poor bioavailability, safety and quality-control issues, and a lack of standardized evaluation systems, they represent promising lead resources for antibabesial drug discovery and warrant further investigation to support their translational development.