Transcription Factor Forkhead Box P (Foxp) 1 Reduces Brain Damage During Cerebral Ischemia-Reperfusion Injury in Mice Through FUN14 Domain-containing Protein 1

Yang Li; Yang Changhong; Yang Liyu; Meng Changchang; Linggao Zeng; Li Yue; Zhao Jing

doi:10.1016/j.neuroscience.2023.07.029

Transcription Factor Forkhead Box P (Foxp) 1 Reduces Brain Damage During Cerebral Ischemia-Reperfusion Injury in Mice Through FUN14 Domain-containing Protein 1

Neuroscience. 2023 Oct 15:530:1-16. doi: 10.1016/j.neuroscience.2023.07.029. Epub 2023 Aug 23.

Authors

Yang Li¹, Yang Changhong², Yang Liyu³, Meng Changchang⁴, Linggao Zeng⁵, Li Yue⁶, Zhao Jing⁷

Affiliations

¹ Department of Pathophysiology, The School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
² Department of Bioinformatics, College of Basic Medicine, Chongqing Medical University, Chongqing, China.
³ Department of Pathology, Chongqing Medical University, Chongqing 400016, China.
⁴ Department of Pathophysiology, The School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
⁵ Chongqing Institute for Food and Drug Control, Chongqing 401121, China; NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing 401121, China.
⁶ Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
⁷ Department of Pathophysiology, The School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China. Electronic address: zhaojing@cqmu.edu.cn.

PMID: 37625686
DOI: 10.1016/j.neuroscience.2023.07.029

Abstract

Mitophagy plays a significant role in modulating the activation of pyrin domain-containing protein 3 (NLRP3) inflammasome, which is a major contributor to the inflammatory response that exacerbates cerebral ischemia-reperfusion (I/R) injury. Despite this, the transcriptional regulation mechanism that governs mitophagy remains unclear. This study sought to explore the potential mechanism of Forkhead Box P1 (Foxp1) and its impact on cerebral I/R injury. We investigated the potential neuroprotective role of Foxp1 in cerebral I/R injury by the middle cerebral artery occlusion (MCAO) mouse model. Additionally, we assessed whether FUN14 domain-containing protein 1 (FUNDC1) could rescue the protective effect of Foxp1. Our results showed that overexpression of Foxp1 prevented brain damage during cerebral I/R injury and promoted NLRP3 inflammasome activation, whereas knockdown of Foxp1 had the opposite effect. Notably, Foxp1 overexpression directly promotes FUNDC1 expression, enhanced mitophagy activation, and inhibited the inflammatory response mediated by the NLRP3 inflammasome. Furthermore, we confirmed through chromatin immunoprecipitation (ChIP) and luciferase reporter assays that FUNDC1 is a direct target gene of Foxp1 downstream. Furthermore, the knockdown of FUNDC1 reversed the increased activation of mitophagy and suppressed NLRP3 inflammasome activation induced by Foxp1 overexpression. Collectively, our findings suggest that Foxp1 inhibits NLRP3 inflammasome activation through FUNDC1 to reduce cerebral I/R injury.

Keywords: FUN14 domain-containing protein 1; cerebral ischemia/reperfusion; forkhead box P 1; mitochondrial autophagy; nod-like receptor protein 3 inflammasome.