Eprinomectin Inhibits Leishmania by Inducing Mitochondrial Dysfunction and Cell Cycle Arrest

Introduction Leishmaniasis remains a significant global health challenge, with current therapies often hampered by toxicity, resistance, and high cost. In this study, we investigated the antileishmanial potential of eprinomectin, a veterinary macrocyclic lactone, to address unmet therapeutic needs. Objectives This study aimed to evaluate the efficacy of eprinomectin against Leishmania , elucidate its underlying mechanisms of action, and explore its potential as a starting point for antileishmanial drug development. Methods The antileishmanial activity of eprinomectin was assessed using in vitro and in vivo models. Mechanistic studies included scanning electron microscopy (SEM) to observe morphological changes, transcriptomic profiling to analyze metabolic pathway alterations, and measurements of reactive oxygen species (ROS). Parasite burden and immune responses were further evaluated in infected mice through histopathology and quantitative assays. Results Eprinomectin exhibited selective activity against Leishmania . SEM imaging suggested division‐related morphological abnormalities, consistent with direct antiproliferative effects. Treatment significantly reduced parasite load and antigen levels in vivo. Transcriptomic analysis suggested mitochondrial dysfunction via downregulation of oxidative phosphorylation (OXPHOS), increased ROS, metabolic stress, and S‐phase cell cycle arrest. Conclusions Eprinomectin demonstrates multimodal antileishmanial effects primarily through direct parasiticidal mechanisms. Its efficacy in reducing parasite burden and disrupting critical metabolic and cell cycle processes supports its potential as a starting point for antileishmanial drug development. These findings support further investigation into the translational potential of eprinomectin, including combination strategies with existing leishmaniasis treatments.