Pentalinonsterol at the Host-Parasite Interface: Antileishmanial Activity, Host Immunomodulation, and Unresolved Mechanisms.

Leishmaniasis remains difficult to treat because available therapies are constrained by toxicity, administration burden, variable efficacy, cost, and drug resistance. This critical narrative review evaluates the preclinical evidence for pentalinonsterol (PEN), a plant-derived cholestane-type steroidal ketone originally isolated from the Mayan medicinal plant Pentalinon andrieuxii. Experimental studies demonstrate PEN activity against Leishmania promastigotes and intracellular amastigotes, together with marked parasite ultrastructural injury; however, no parasite molecular target has been validated. PEN also modulates host-cell responses involving NF-κB/AP-1 signalling, antigen presentation and co-stimulatory markers, dendritic-cell IL-12 production, T-cell IFN-γ responses, MAPK-cPLA₂ signalling, and Nrf2-associated transcriptional and redox responses. These findings establish host-active pharmacology but do not demonstrate that any PEN-responsive host pathway is required for parasite clearance. Liposomal PEN reduced parasite burdens in experimental visceral leishmaniasis, although its pharmacokinetic, tissue-delivery, safety, or efficacy advantage over free PEN has not been established. Overall, the available evidence remains preclinical: parasite-directed activity and host-cell modulation have each been demonstrated, but their molecular targets, causal interdependence, relative contribution to parasite clearance, and temporal relationship remain unresolved. PEN is therefore most appropriately regarded as a putative dual-action antileishmanial natural product for which the proposed dual mechanism requires direct experimental validation.