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

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. <i>In vitro</i> 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.

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Journal
iScience
Published
2025-08-22
DOI
https://doi.org/10.1016/j.isci.2025.113423
Primary Topic
Congenital gastrointestinal and neural anomalies
Type
article
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0.00
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article

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

Qiangye Zhang, Aiwu Li, Dong Sun, Yaru Mou et al.
iScience
Congenital gastrointestinal and neural anomalies
article

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

Qiangye Zhang, Aiwu Li, Dong Sun, Yaru Mou, Pengyi Hou, Qiongqian Xu, Weijing Mu, Xixi He, Xue Ren, Jian Wang, Xiaoyang Liu, Yixuan Wang, Chunhong Ma, Jichang Han, Dongming Wang, Xintao Zhang
article en

Abstract

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. <i>In vitro</i> 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.

iScienceVol. 28(9)
Jishou University (CN), Shandong Provincial Hospital (CN), Qilu Hospital of Shandong University (CN), Shandong First Medical University (CN)
Openalex Percentile: Top 64%
Congenital gastrointestinal and neural anomalies
DOIOpen Access PDFOpenAlex
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FGL2-induced metabolic dysregulation in enteric neural crest cells provides insight into Hirschsprung disease pathogenesis — Qiangye Zhang, Aiwu Li, et al. · iScience (2025) | TGRS Research Map | TGRS