The mevalonate and methylerythritol phosphate pathways as therapeutic targets in protozoan parasites: from moonlighting enzymes to metabolic plasticity

The interplay between metabolic pathways and immune responses is critical for understanding host-parasite interactions in protozoan infections. This review examines the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways—key routes for isoprenoid synthesis essential for sterol production and bioactive compounds. Beyond sustaining parasite survival, these pathways directly influence host immune signaling cascades, including NF-κB, MAPK, PI3K/Akt, and mTOR. A critical conceptual distinction is introduced: genuine “moonlighting” functions—where a single enzyme performs two distinct molecular roles—are currently documented only for mevalonate kinase in trypanosomatids. Leishmania donovani secretes mevalonate kinase (LdMVK), which has been associated with modulation of macrophage inflammatory signaling and attenuation of NF-κB-dependent cytokine responses. Similarly, Trypanosoma cruzi mevalonate kinase (TcMVK) alters host calcium signaling and MAPK activation, promoting parasite invasion. By contrast, most effects described in the literature—such as trained immunity induction or Th1/Th2 skewing following statin treatment—represent pleiotropic consequences of canonical pathway disruption. Therapeutically, the absence of the MEP pathway in humans and structural divergence of parasitic MVA enzymes enable selective targeting. Strategies include drug repurposing (statins, bisphosphonates), novel enzyme inhibitors, and immunomodulatory approaches. However, parasitic metabolic plasticity and host toxicity remain challenges, supporting “double-hit” combination therapies that simultaneously disrupt parasite metabolism and block salvage pathways to overcome resistance. By integrating metabolic essentiality with immune signaling, MVA/MEP pathways emerge as multifunctional hubs offering promising avenues for precision therapies and vaccines against neglected tropical diseases.