Reg4, also known as Regenerating islet-derived 4, is a member of the calcium-dependent lectin gene superfamily. It is involved in multiple biological processes, including inflammation, infection, and tumorigenesis. REG4 can enhance macrophage polarization to M2 via activation of the epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding pathway, and it kills inflammatory Escherichia coli [1]. In tumorigenesis, its overexpression is observed in various cancers, and it promotes cancer cell proliferation, anti-apoptosis, chemoradioresistance, migration, and invasion through EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways [1].

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 [2]. The C-X-C motif ligand 12 (CXCL12)/C-X-C motif receptor 4 (CXCR4) axis is sustained and activated in Reg4 -deficient pancreas, and the detrimental effects can be attenuated by the CXCR4 antagonist plerixafor. Mechanistically, Reg4 may mediate its function via binding to its receptor exostosin-like glycosyltransferase 3 (Extl3) [2]. In pancreatic regeneration after pancreatitis, Reg4 knockdown significantly impairs pancreatic regeneration, affecting acinar-to-ductal metaplasia and the resolution of pancreatitis, and it exerts its function through regulating Notch activation [3]. In intestinal-specific Reg4 -deficient mice fed a high-fat diet, there is increased intestinal fat absorption, leading to obesity and hepatic steatosis, along with enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of intestinal fat transporters [4].

In conclusion, Reg4 plays crucial roles in inflammation, infection, tumorigenesis, pancreatitis, pancreatic regeneration, and intestinal fat absorption. The use of Reg4-KO or CKO mouse models has revealed its functions in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases such as pancreatitis, cancer, and liver steatosis.