TXNRD1-driven enteric glial remodeling promotes neuronal dysfunction in Hirschsprung disease.

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.