Abstract / Summary
Hirschsprung disease (HSCR) is characterized by distal intestinal aganglionosis and persistent dysfunction of the enteric nervous system after surgical treatment. Here, we integrated single-cell transcriptomics, network-based virtual perturbation analysis, proteomics, human tissue validation, enteric glial cell assays, neuron-glia co-culture systems, and an Ednrb conditional knockout (cKO) mouse model to investigate TXNRD1-dependent enteric glial remodeling in HSCR. We found that thioredoxin reductase 1 (TXNRD1) enrichment was associated with expansion of an SPP1-high/CXCL9-low enteric glial state and selective ERK/MAPK activation. TXNRD1 overexpression increased oxidative stress, impaired enteric glial migration and neurotrophic support, and induced neuronal dysfunction through suppression of GDNF/GFRα1/RET signaling. TXNRD1 inhibition alleviated HSCR-like phenotypes in Ednrb cKO mice. These findings identify TXNRD1-driven redox-dependent enteric glial remodeling as a mechanism contributing to neuronal dysfunction and HSCR progression.