Piplartine as an Innovative Natural Product With Dual Antiparasitic and Immunomodulatory Actions.

Neglected tropical diseases (NTDs) remain a major global health burden, disproportionately affecting low- and middle-income regions and demanding innovative therapeutic strategies. This review summarizes current evidence on piplartine (piperlongumine), a naturally occurring amide from Piper species with broad antiparasitic and immunomodulatory properties. Studies on Schistosoma mansoni, Angiostrongylus cantonensis, Leishmania spp., Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii demonstrate potent activity at micromolar levels, associated with disruption of parasite redox homeostasis. In host immune cells, piplartine modulates NF-κB and Nrf2 signaling, inhibits the immunoproteasome, and promotes antioxidant and anti-inflammatory responses. These dual properties suggest that piplartine may influence both parasite survival and host immunopathology through redox-sensitive mechanisms, although direct cause-effect relationships during parasitic infection remain to be experimentally established. The compound's favorable drug-likeness, oral bioavailability, and selective toxicity profile highlight its potential as a multitarget scaffold for the development of next-generation therapeutics against neglected tropical and immune-related diseases.