Cyclophilins as key players in protozoan parasite infections.

Cyclophilins (Cyps), a highly conserved family of immunophilins with peptidyl-prolyl cis-trans isomerase (PPIase) activity, play pivotal roles in protein folding, cell signaling, immune modulation, and host-pathogen interactions. In protozoan infections, parasite-encoded Cyps are essential for immune evasion, oxidative stress regulation, and pathogen survival. This review highlights the multifaceted roles of Cyps in Plasmodium, Toxoplasma, Trypanosoma, and Leishmania, with particular emphasis on their involvement in host cell invasion, replication, and immunomodulation. Key Cyps-such as Plasmodium Cyp19B, Toxoplasma Cyp18, Leishmania major Cyp19, and Trypanosoma Cyp19-have been implicated in oxidative stress management, host cell entry, and immune suppression. Given these critical functions, Cyps represent promising therapeutic targets; cyclosporine A (CsA) and its analogs inhibit parasite proliferation by disrupting Cyp activity. Moreover, parasite-derived Cyps show potential as vaccine candidates, eliciting protective immunity in models of leishmaniasis, toxoplasmosis, and Chagas disease. Host Cyps further influence infection outcomes by modulating mitochondrial permeability, cytokine production, and macrophage polarization. For example, mitochondrial CypD regulates cell death pathways in Trypanosoma cruzi-induced cardiac pathology. Despite these advances, further research is required to validate the therapeutic and prophylactic potential of Cyps. Future studies should investigate stage-specific Cyp functions, host-pathogen interactions, and the development of nonimmunosuppressive Cyp inhibitors to advance targeted antiparasitic strategies.