Neurokinin 1 receptor inhibition alleviated mitochondrial dysfunction via restoring purine nucleotide cycle disorder driven by substance P in acute pancreatitis.
10.1016/j.apsb.2025.03.037
- Author:
Chenxia HAN
1
;
Lu LI
1
;
Lin BAI
2
;
Yaling WU
3
;
Jiawang LI
1
;
Yiqin WANG
1
;
Wanmeng LI
3
;
Xue REN
3
;
Ping LIAO
4
;
Xiaoting CHEN
5
;
Yaguang ZHANG
6
;
Fengzhi WU
7
;
Feng LI
8
;
Dan DU
1
;
Qing XIA
1
Author Information
1. West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Histology and Imaging Platform, Research Core Facility, West China Hospital, Sichuan University, Chengdu 610041, China.
3. Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China.
4. Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China.
5. Animal Experimental Center, West China Hospital, Sichuan University, Chengdu 610213, China.
6. Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China.
7. Journal Center, Beijing University of Chinese Medicine, Beijing 100029, China.
8. School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
- Publication Type:Journal Article
- Keywords:
Acute pancreatitis;
Fumarate;
Magnolol;
Mitochondrial dysfunction;
Neurokinin 1 receptor;
Purine nucleotide cycle;
Substance P;
β-Arrestin1
- From:
Acta Pharmaceutica Sinica B
2025;15(6):3025-3040
- CountryChina
- Language:English
-
Abstract:
Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.
