FGL2-induced metabolic dysregulation in enteric neural crest cells provides insight into Hirschsprung disease...

Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of enteric neural crest cells (ENCCs) in aganglionic segments of the intestine. Here, we report that fibrinogen-like protein 2 (FGL2) is upregulated in aganglionic colon tissues from patients with HSCR. In vitro experiments using primary ENCCs isolated from embryonic mouse colon showed that FGL2 stimulation increased ENCC apoptosis. Mechanistically, FGL2 enhances oxidative phosphorylation (OXPHOS) via the activation of the JAK2-STAT3 signaling pathway, leading to reactive oxygen species (ROS) accumulation and subsequent apoptosis. Overall, these findings identify FGL2 as a potential pathogenic factor in HSCR that impacts ENCC survival and provide mechanistic insight into the metabolic regulation of ENCCs in the context of HSCR.