Natural product-based therapeutic strategies against Leishmania: mechanistic insights and emerging host-directed approaches.

Leishmaniasis remains a major neglected tropical disease, while available treatments are constrained by toxicity, cost, prolonged administration, relapse, variable geographical efficacy, and emerging drug resistance. Natural products provide structurally diverse antileishmanial candidates capable of acting through both parasite-directed and host-mediated mechanisms. This review critically evaluates natural compounds targeting parasite membrane integrity, mitochondrial function, redox homeostasis, arginase and polyamine metabolism, sterol biosynthesis, and replication-associated enzymes. It also examines their immunomodulatory effects, including macrophage activation, nitric oxide and reactive oxygen species production, promotion of T-helper-1-associated responses, and suppression of parasite-favorable immune pathways. Particular attention is given to emerging host-directed strategies involving microRNAs that regulate autophagy, inflammatory signaling, macrophage polarization, and host lipid metabolism. Functional evidence supports selected miRNA-target axes, including miR-30a-3p-BECN1, miR-330-5p-SPTLC1, miR-1303-HMGCR, and miR-874-3p-HMGCS1. However, the therapeutic consequences of miRNA modulation are species- and disease-form-dependent, and direct evidence connecting natural-product activity with specific miRNA-mediated mechanisms remains limited. Although several natural products and natural product-drug combinations demonstrate activity against intracellular amastigotes and in animal models, much of the literature still relies on promastigote assays, crude extracts, molecular docking, or correlative immune and transcriptomic measurements. Clinical translation will require chemical standardization, direct target validation, macrophage-selective delivery, pharmacokinetic and toxicological evaluation, and demonstration of efficacy in clinically relevant infection models. Overall, natural products and host-directed interventions represent complementary therapeutic strategies, but progress will depend on moving from descriptive screening toward standardized, mechanism-based, and translationally relevant investigation.