Theasaponin E1 Induce Ferroptotic Cell Death in Pomacea canaliculata through Coordinated Disruption of Cholesterol Homeostasis and Sphingolipid Metabolism

The invasive golden apple snail, Pomacea
canaliculate, threatens agriculture and public health
globally. This study systematically
investigates the molluscicidal mechanism of theasaponin E1 (TSE1),
a tea saponin monomer. TSE1 exhibited concentration- and time-dependent
toxicity. Transcriptomics revealed dysregulation of cholesterol homeostasis,
including marked upregulation of squalene monooxygenase, lanosterol synthase, and cholesterol
catabolic enzymes (CYP3A24, CYP2U1). Concurrently, sphingolipid metabolism exhibited dual perturbation,
with both sphingomyelin accumulation and ceramide elevation mediated
by differential expression of DEGS2 and MOXD1. Ultrastructural analysis showed mitochondrial cristae dissolution
and membrane rupture, with ferroptosis activation through voltage-dependent
anion channel 2 upregulation and oxidative stress. Notably, granulocytes
displayed distinct resistance to TSE1-induced cytotoxicity, suggesting
cell-type specific protective mechanisms. These findings establish
that TSE1 exerts its molluscicidal effect through coordinated disruption
of lipid homeostasis, culminating in iron-dependent cell death. The
conserved ferroptotic pathway and cell-selective vulnerabilities identified
in this study provide critical insights for developing targeted, environmentally
sustainable molluscicides.