Angiogenin-4 (ANG4) in swine (Sus scrofa) and mouse (Mus musculus) is a member of the RNase A superfamily and is identical at the amino acid sequence level in these two species, enabling cross-species applicability in comparative research. ANG4 is primarily expressed in the gastrointestinal tract, particularly by Paneth cells in the small intestine, where it plays a key role in innate mucosal immunity rather than classical angiogenesis. It possesses ribonuclease activity and exhibits antimicrobial properties against select bacterial and fungal species, contributing to maintenance of intestinal microbial homeostasis and epithelial barrier defense. ANG4 expression is regulated by microbial colonization and immune signaling pathways, including Th2-associated cytokines such as IL-13, linking it to type 2 immune responses and host–microbiota interactions. In both swine and mouse models, ANG4 is upregulated during helminth infection, inflammatory bowel disease–like conditions, intestinal injury, and immune stimulation. Due to the physiological and gastrointestinal similarities between pigs and humans, and the extensive use of mouse models in immunology, characterization of ANG4 in swine and mouse provides valuable insight into Paneth cell biology, mucosal immunity, microbiome regulation, and intestinal inflammatory disease mechanisms in translational research settings.