Fam3d, a cytokine-like protein, is involved in multiple biological functions. It is associated with pathways related to metabolism, inflammation, and vasoregulation, playing an important role in maintaining physiological homeostasis [1-10]. Genetic models, such as KO/CKO mouse models, have been crucial in understanding its functions [1-10].

In hypertension, Fam3d deficiency significantly ameliorates angiotensin II-induced hypertension in mice. Mechanistically, Fam3d causes endothelial nitric oxide synthase (eNOS) uncoupling through formyl peptide receptor 1 (FPR1) and FPR2-mediated oxidative stress, exacerbating hypertension [1]. In non-alcoholic fatty liver disease (NAFLD), hepatic Fam3d overexpression in obese mice ameliorated hyperglycemia and steatosis, while Fam3d-deficient mice had exaggerated symptoms after high-fat diet-feeding. Fam3d activates the FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation [2]. In the context of glucose metabolism, gut-secreted Fam3D improves fasting blood glucose levels, glucose tolerance, and insulin sensitivity when overexpressed in diet-induced obese mice [3]. Also, in pancreatic alpha cells, Fam3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling [5]. In colon, Fam3D deficiency is associated with impaired colonic mucosa integrity, increased epithelial hyper-proliferation, and increased sensitivity to chemically induced colitis [4].

In conclusion, Fam3d plays essential roles in metabolism, blood pressure regulation, and maintaining colon homeostasis. Studies using Fam3d KO/CKO mouse models have revealed its contributions to diseases such as hypertension, NAFLD, and colitis-associated cancer, providing potential therapeutic targets for these conditions.