Reg4, short for regenerating islet-derived 4, is a member of the calcium-dependent lectin gene superfamily. It is involved in multiple biological processes. REG4 can enhance macrophage polarization to M2 via activation of the epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding pathway, playing a role in infection and inflammation. It is also closely linked to tumorigenesis, participating in cell proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, and cancer stemness through pathways like EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 [1,3].

In pancreatitis, Reg4-deficient mice show increased inflammatory infiltrates, mitochondrial cell death, and fibrosis in acute pancreatitis, and aggravated inflammation, fibrosis, and inhibited compensatory cell proliferation in chronic pancreatitis. These detrimental effects can be rescued by recombinant Reg4 protein or the CXCR4 antagonist plerixafor. Mechanistically, Reg4 may mediate its function in pancreatitis via binding to its receptor Extl3 [2]. In pancreatic regeneration after pancreatitis, Reg4 knockdown significantly impairs the process, affecting acinar-to-ductal metaplasia and the resolution of pancreatitis, and it exerts its function through regulating Notch activation [4]. In intestinal-specific Reg4-deficient mice fed a high-fat diet, there is increased intestinal fat absorption, making them prone to obesity and hepatic steatosis. Administration of REG4 reduces fat absorption in cultured intestinal cells possibly via the CaMKK2-AMPK pathway [5].

In conclusion, Reg4 plays essential roles in inflammation, cancer, pancreatic regeneration, and intestinal fat absorption. Gene-knockout mouse models, such as Reg4-deficient and intestinal-specific Reg4-deficient mice, have been crucial in revealing these functions, contributing to understanding the mechanisms in pancreatitis, pancreatic regeneration, and the development of liver steatosis. These findings suggest Reg4 could be a potential target for treating related diseases [2,4,5].

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/