PMID- 38523594
OWN - NLM
STAT- Publisher
LR  - 20240325
IS  - 1365-2184 (Electronic)
IS  - 0960-7722 (Linking)
DP  - 2024 Mar 25
TI  - Rack1-mediated ferroptosis affects hindgut development in rats with anorectal 
      malformations: Spatial transcriptome insights.
PG  - e13618
LID - 10.1111/cpr.13618 [doi]
AB  - Anorectal malformation (ARM), a common congenital anomaly of the digestive tract, 
      is a result of insufficient elongation of the urorectal septum. The cytoplasmic 
      protein Receptor of Activated C-Kinase 1 (Rack1) is involved in embryonic neural 
      development; however, its role in embryonic digestive tract development and ARM 
      formation is unexplored. Our study explored the hindgut development and cell 
      death mechanisms in ARM-affected rats using spatial transcriptome analysis. We 
      induced ARM in rats by administering ethylenethiourea via gavage on gestational 
      day (GD) 10. On GDs 14-16, embryos from both normal and ARM groups underwent 
      spatial transcriptome sequencing, which identified key genes and signalling 
      pathways. Rack1 exhibited significant interactions among differentially expressed 
      genes on GDs 15 and 16. Reduced Rack1 expression in the ARM-affected hindgut, 
      verified by Rack1 silencing in intestinal epithelial cells, led to increased P38 
      phosphorylation and activation of the MAPK signalling pathway. The suppression of 
      this pathway downregulated Nqo1 and Gpx4 expression, resulting in elevated 
      intracellular levels of ferrous ions, reactive oxygen species (ROS) and lipid 
      peroxides. Downregulation of Gpx4 expression in the ARM hindgut, coupled with 
      Rack1 co-localisation and consistent mitochondrial morphology, indicated 
      ferroptosis. In summary, Rack1, acting as a hub gene, modulates ferrous ions, 
      lipid peroxides, and ROS via the P38-MAPK/Nqo1/Gpx4 axis. This modulation induces 
      ferroptosis in intestinal epithelial cells, potentially influencing hindgut 
      development during ARM onset.
CI  - (c) 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem 
      Cell and Regenerative Medicine and John Wiley & Sons Ltd.
FAU - Wang, Chen-Yi
AU  - Wang CY
AUID- ORCID: 0000-0003-0944-3222
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Li, Mu-Yu
AU  - Li MY
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Li, Si-Ying
AU  - Li SY
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Wei, Xiao-Gao
AU  - Wei XG
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Dong, Nai-Xuan
AU  - Dong NX
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Liu, Shu-Ting
AU  - Liu ST
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Yuan, Zheng-Wei
AU  - Yuan ZW
AD  - Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital 
      of China Medical University, Shenyang, China.
FAU - Li, Bo
AU  - Li B
AUID- ORCID: 0000-0002-8298-8344
AD  - Division of General and Thoracic Surgery, The Hospital for Sick Children, 
      Toronto, Canada.
FAU - Pierro, Agostino
AU  - Pierro A
AD  - Division of General and Thoracic Surgery, The Hospital for Sick Children, 
      Toronto, Canada.
FAU - Tang, Xiao-Bing
AU  - Tang XB
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
FAU - Bai, Yu-Zuo
AU  - Bai YZ
AUID- ORCID: 0000-0002-0647-6195
AD  - Department of Pediatric Surgery, Shengjing Hospital of China Medical University, 
      Shenyang, China.
LA  - eng
GR  - Me56/Shengjing Hospital/
GR  - 82070530/National Natural Science Foundation of China/
GR  - 82170530/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20240325
PL  - England
TA  - Cell Prolif
JT  - Cell proliferation
JID - 9105195
SB  - IM
EDAT- 2024/03/25 06:42
MHDA- 2024/03/25 06:42
CRDT- 2024/03/25 04:13
PHST- 2024/02/04 00:00 [revised]
PHST- 2023/12/19 00:00 [received]
PHST- 2024/02/07 00:00 [accepted]
PHST- 2024/03/25 06:42 [medline]
PHST- 2024/03/25 06:42 [pubmed]
PHST- 2024/03/25 04:13 [entrez]
AID - 10.1111/cpr.13618 [doi]
PST - aheadofprint
SO  - Cell Prolif. 2024 Mar 25:e13618. doi: 10.1111/cpr.13618.