Functional characterization of TGFβ/BMP receptors in <i>Echinococcus granulosus sensu stricto</i> : implications for parasite survival and therapeutic targeting

Cystic echinococcosis (CE), a zoonosis caused by the larval stage of the tapeworm <i>Echinococcus granulosus sensu lato</i> (<i>E. granulosus s.l</i>.), remains a global health burden. Despite the conserved role of the transforming growth factor beta (TGFβ)/Smad signaling in cellular regulation across species, the molecular mechanisms of TGFβ/bone morphogenetic proteins (BMP) receptors in <i>E. granulosus sensu stricto</i> (<i>E. granulosus s.s</i>.) are poorly understood. The TGFβ/BMP receptors of <i>E. granulosus s.s</i>. were cloned and molecularly characterized. The positive binding interaction between receptors and their ligands was identified using the yeast two-hybrid system. To investigate the role of TGFβ/BMP signaling in <i>E. granulosus s.s</i>. development and survival, LDN193189 was employed in both the <i>in vitro</i> co-culture system and subsequent <i>in vivo</i> bioassays to investigate its pharmacological effects. Both receptors, <i>E. granulosus</i> type I receptor (EgTR1) and type II receptor (EgTR2), were characterized in <i>E. granulosus s.s</i>. and expressed during the larval stages, with <i>egtr2</i> showing peak transcriptional levels in activated protoscoleces (PSCs), 40-fold higher than those in cysts. <i>In situ</i> immunofluorescence analysis demonstrated a predominant localization of EgTR1 and EgTR2 within the tegument, suckers, and hooks of PSCs, as well as in the germinal layer of larval cysts. Yeast two-hybrid analysis revealed that EgTR2 interacted with EgTR1 and HsBMP2, but not with HsTGFβ. LDN193189 treatment significantly suppressed the viability of PSCs. <i>In vivo</i> bioassays in mice demonstrated a notable reduction in the weight of cysts in the LDN193189-treated group compared with the dimethyl sulfoxide-treated group. Our results suggest that EgTR1 and EgTR2 regulate <i>E. granulosus s.s</i>. development<i>,</i> identifying TGFβ/BMP signaling as a therapeutic target for CE.IMPORTANCECystic echinococcosis (CE), a neglected zoonosis caused by <i>E. granulosus s.l</i>., inflicts severe morbidity and economic losses globally. While transforming growth factor beta/bone morphogenetic proteins (TGFβ/BMP) signaling regulates cellular processes across species, its functional role in <i>E. granulosus s.s.</i> remains unexplored. Here, we elucidate the molecular basis of TGFβ/BMP receptor signaling in <i>E. granulosus s.s.</i>, revealing that <i>E. granulosus</i> type I receptor (EgTR1) and type II receptor (EgTR2) orchestrate larval development through species-specific ligand interactions. Our findings demonstrate that EgTR2 interacts with Human BMP2 (HsBMP2), establishing a unique parasitic adaptation mechanism. Pharmacological inhibition using LDN193189 caused the suppression of parasite viability <i>in vitro</i> and reduced cyst weight <i>in vivo</i>, validating these receptors as druggable targets. This study provides the evidence linking TGFβ/BMP receptor dynamics to parasitic survival strategies, while identifying a clinically accessible therapeutic avenue for CE. The discovery bridges a critical gap in parasitic helminth biology and advances precision medicine approaches for combating this neglected tropical disease.