NREP, also known as neuronal regeneration-related protein or P311, is a multifunctional protein involved in embryonic development, regeneration, and human disease [3]. It participates in the transformation of neural, muscle, and fibroblast cells and in smooth muscle myogenesis [8]. NREP has been associated with multiple biological processes and signaling pathways, such as the TGF-β1/Smad2/3 pathway [6].

In arsenite-related idiopathic pulmonary fibrosis (As-IPF), the levels of m6A-modified NREP were elevated in alveolar epithelial cells (AECs), promoting the fibroblast-to-myofibroblast transition (FMT) via the YTHDF1/m6A/NREP axis [1]. In non-alcoholic fatty liver disease (NAFLD), NREP knockdown in primary human hepatocytes induced transcriptomic remodeling, affecting pathways related to phosphatidylinositol signaling and one-carbon metabolism, along with changes in lipid profiles [2]. In breast cancer, under hypoxic conditions, HIF-1α directly binds to the NREP promoter to upregulate its transcription, and NREP promotes cell growth, metastasis, and glycolysis [3]. In gastric cancer, NREP is upregulated, promoting cell proliferation, angiogenesis, migration, and invasion, and is associated with poor survival and tumor-associated immune infiltration [4,5]. In osteoarthritis (OA), NREP is downregulated in damaged articular cartilage, and its knockdown in normal chondrocytes reduces their proliferative capacity by inactivating the TGF-β1/Smad2/3 pathway [6]. In cerebral ischemia, miR-124-3p alleviates neuroaxonal damage by enhancing Nrep expression [7]. In pigs, the NREP gene shows different expression levels between Czech Large White pigs and wild boars, and certain polymorphisms are associated with meat production traits [8].

In summary, NREP plays crucial roles in multiple biological processes and disease conditions, including fibrosis, liver disease, cancer, and neurodegenerative and joint diseases. The studies on NREP, especially those using loss-of-function approaches, have enhanced our understanding of its functions in these disease areas, potentially providing new therapeutic targets [1-10].

References:

1. Wang, Peiwen, Xie, Daxiao, Xiao, Tian, Zhang, Aihua, Liu, Qizhan. 2023. H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP. In Journal of hazardous materials, 461, 132582. doi:10.1016/j.jhazmat.2023.132582. https://pubmed.ncbi.nlm.nih.gov/37742376/

2. De Jesus, Dario F, Kimura, Tomohiko, Gupta, Manoj K, Kulkarni, Rohit N. 2023. NREP contributes to development of NAFLD by regulating one-carbon metabolism in primary human hepatocytes. In Cell chemical biology, 30, 1144-1155.e4. doi:10.1016/j.chembiol.2023.06.001. https://pubmed.ncbi.nlm.nih.gov/37354909/

3. Ruan, Yuxia, Qiao, Jianghua, Wang, Jiabin, Liu, Zhenzhen. 2024. NREP, transcriptionally upregulated by HIF-1α, aggravates breast cancer cell growth and metastasis by promoting glycolysis. In Cell death discovery, 10, 210. doi:10.1038/s41420-024-01951-2. https://pubmed.ncbi.nlm.nih.gov/38697993/

4. Li, Qian, Fu, Lei, Wu, Daoyuan, Wang, Jufeng. 2022. NREP is a Diagnostic and Prognostic Biomarker, and Promotes Gastric Cancer Cell Proliferation and Angiogenesis. In Biochemical genetics, 61, 669-686. doi:10.1007/s10528-022-10276-7. https://pubmed.ncbi.nlm.nih.gov/36094607/

5. Liu, Yuan-Jie, Zeng, Shu-Hong, Hu, Yi-Dou, Zhang, Yong-Hua, Li, Jie-Pin. 2021. Overexpression of NREP Promotes Migration and Invasion in Gastric Cancer Through Facilitating Epithelial-Mesenchymal Transition. In Frontiers in cell and developmental biology, 9, 746194. doi:10.3389/fcell.2021.746194. https://pubmed.ncbi.nlm.nih.gov/34746143/

6. Liu, Yang, Liu, Mengrou, Zhang, Chengming, Li, Pengcui, Yang, Ziquan. 2023. The silencing of NREP aggravates OA cartilage damage through the TGF-β1/Smad2/3 pathway in chondrocytes. In Journal of orthopaedic translation, 44, 26-34. doi:10.1016/j.jot.2023.11.004. https://pubmed.ncbi.nlm.nih.gov/38179126/

7. Huang, Peng, Wei, Songren, Ren, Jing, Xu, Jiangping, Liu, Guoqing. 2022. MicroRNA-124-3p alleviates cerebral ischaemia-induced neuroaxonal damage by enhancing Nrep expression. In Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 32, 106949. doi:10.1016/j.jstrokecerebrovasdis.2022.106949. https://pubmed.ncbi.nlm.nih.gov/36535134/

8. Knoll, Aleš, Nesvadbová, Michaela, Urban, Tomáš. 2021. The expression pattern, polymorphisms and association analyses of the porcine NREP gene. In Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie, 139, 62-70. doi:10.1111/jbg.12646. https://pubmed.ncbi.nlm.nih.gov/34487372/