Reg4, short for Regenerating islet-derived 4, is a member of the calcium-dependent lectin gene superfamily. It is involved in multiple biological functions, such as regulating cell proliferation, apoptosis, and differentiation. It functions through various pathways including EGFR/Akt/activator protein-1, Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4, and Notch signaling. It is of great importance in inflammation, tumorigenesis, and tissue regeneration [1,3,4]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In pancreatitis, Reg4-deficient mice show increased inflammatory infiltrates, mitochondrial cell death, and fibrosis in acute pancreatitis, and aggravated inflammation and fibrosis with inhibited compensatory cell proliferation in chronic pancreatitis. This indicates that Reg4 exerts a therapeutic effect during pancreatitis by limiting inflammation and fibrosis and improving cellular regeneration [2]. In pancreatic regeneration after pancreatitis, Reg4 knockdown significantly impairs pancreatic regeneration, affecting acinar-to-ductal metaplasia and the resolution of pancreatitis, suggesting its role in regulating pancreatic regeneration through Notch activation [4]. Intestinal-specific Reg4-deficient mice fed a high-fat diet have increased intestinal fat absorption, making them prone to obesity and hepatic steatosis, demonstrating the role of Reg4 in preventing liver steatosis by reducing intestinal fat absorption [5].

In conclusion, Reg4 plays essential roles in inflammation, tissue regeneration, and metabolic regulation. The use of Reg4 KO/CKO mouse models has revealed its functions in pancreatitis, pancreatic regeneration, and liver steatosis, providing potential therapeutic targets for these diseases.

References:

1. Zheng, Hua-Chuan, Xue, Hang, Zhang, Cong-Yu. 2022. REG4 promotes the proliferation and anti-apoptosis of cancer. In Frontiers in cell and developmental biology, 10, 1012193. doi:10.3389/fcell.2022.1012193. https://pubmed.ncbi.nlm.nih.gov/36172286/

2. Yan, Weihui, Wang, Ying, Lu, Ying, Cai, Wei, Xiao, Yongtao. 2024. Reg4 deficiency aggravates pancreatitis by increasing mitochondrial cell death and fibrosis. In Cell death & disease, 15, 348. doi:10.1038/s41419-024-06738-y. https://pubmed.ncbi.nlm.nih.gov/38769308/

3. Zhang, Junyan, Zhu, Zhi, Miao, Zhifeng, Xu, Huimian, Wang, Zhenning. 2021. The Clinical Significance and Mechanisms of REG4 in Human Cancers. In Frontiers in oncology, 10, 559230. doi:10.3389/fonc.2020.559230. https://pubmed.ncbi.nlm.nih.gov/33489872/

4. Dai, Juanjuan, He, Yan, Jiang, Mingjie, Wang, Xingpeng, Hu, Guoyong. 2021. Reg4 regulates pancreatic regeneration following pancreatitis via modulating the Notch signaling. In Journal of cellular physiology, 236, 7565-7577. doi:10.1002/jcp.30397. https://pubmed.ncbi.nlm.nih.gov/33899235/

5. Wang, Ying, Yan, Weihui, Lu, Ying, Cai, Wei, Xiao, Yongtao. 2023. Intestinal Reg4 deficiency confers susceptibility to high-fat diet-induced liver steatosis by increasing intestinal fat absorption in mice. In JHEP reports : innovation in hepatology, 5, 100700. doi:10.1016/j.jhepr.2023.100700. https://pubmed.ncbi.nlm.nih.gov/37138677/