Decoding the metabolic checkpoints in helminths: Opportunities for novel anthelmintic drug development.

Carbohydrate metabolism is a universal requirement for all life forms, with glycolysis providing a conserved pathway for energy production. Helminth parasites, including cestodes, trematodes, and nematodes, exhibit remarkable metabolic plasticity that enables survival within nutrient-limited, hypoxic, and immunologically hostile host environments. To adapt, these parasites rely heavily on carbohydrate metabolism, particularly glycolysis and associated anaerobic pathways such as malate dismutation, to sustain ATP generation across different life cycle stages. Infection often leads to the upregulation of key metabolic enzymes, including hexokinase and pyruvate kinase, underscoring the dependence of helminths on glycolytic flux. Host immune responses impose significant metabolic constraints on parasites through nutrient sequestration, oxidative stress, and pro-inflammatory cytokines such as IFN-γ and TNF-α, which disrupt glucose uptake, damage mitochondria, and promote reactive oxygen and nitrogen species production. In response, helminths remodel their metabolic pathways, enhance antioxidant defenses, and promote type-2 immune polarization to maintain homeostasis and ensure survival. These host-parasite metabolic interactions reveal critical vulnerabilities that can be exploited for therapeutic intervention. Current anthelmintics primarily target parasite energy metabolism by disrupting glucose uptake, mitochondrial function, and ATP production, while emerging strategies focus on glycolytic inhibitors and mitochondrial disruptors with improved specificity. This review, we aim to explore highlights the intricate interplay between helminth metabolism and host immunity and emphasizes the potential of targeting metabolic checkpoints to develop next generation anthelmintics, particularly in the context of rising drug resistance and the persistent global burden of helminth infections.