Histatins (Hsts) are cationic and histidine-rich secreted peptides mainly synthesized by saliva glands of humans and higher primates (PubMed : 3286634, PubMed : 3944083). Hsts are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). Hsts can be divided into two major groups according to their biological functions : antimicrobial Hsts (e.g. Hst 5/HTN3) and cell-activating Hsts (e.g. Hst 1/HTN1 and Hst 2/HTN1) (PubMed : 32225006). Hst 1/HTN1 and Hst 2/HTN1 act in different cell types (epithelium, fibroblasts and endothelium) in oral and non-oral mucosa (PubMed : 25903106, PubMed : 28542418, PubMed : 28751526, PubMed : 32225006).. Histatin-1. Hst 1 functions primarily as a wound healing factor by activating cell-surface and cell-cell adhesions, cell spreading and migration and it can also stimulate cellular metabolic activity (PubMed : 18650243, PubMed : 25903106, PubMed : 28542418, PubMed : 28751526, PubMed : 32225006, PubMed : 35970844). Hst 1 is internalized in host cells in a stereospecific and energy-dependent process, which is partially mediated by the G protein-coupled receptors (GPCR)-activated endocytosis (PubMed : 35970844). Internalized Hst 1 is targeted and released via early endosomes trafficking to the mitochondria, where it significantly enhances mitochondrial energy metabolism (PubMed : 32225006, PubMed : 35970844). At the mitochondria, Hst 1 increases mitochondria-ER contacts through binding with ER receptor TMEM97, which also stimulates metabolic activity and cell migration and may as well regulate calcium homeostasis of the cell (PubMed : 32225006, PubMed : 34233061, PubMed : 35970844). Also activates the ERK1/2 signaling pathway to promote cell migration, possibly upon interaction with GPRCs at the plasma membrane (PubMed : 28751526). Also triggers the RIN2/Rab5/Rac1 signaling cascade which activates endothelial cell adhesion, spreading and migration required for angiogenesis in the oral wound healing process, however the receptor that transduces Hst 1 signal has not yet been identified (PubMed : 28751526). Also displays antimicrobial functions against pathogenic yeast Candida albicans, although with less effectiveness than Hst 5 (PubMed : 28751526, PubMed : 3286634, PubMed : 3944083).. His1-(31-57)-peptide. Hst 2 consists of the fragment sequence 12-28 of Hst 1. Similar to Hst 1, actively and stereospecifically internalized in host cells and targeted to the mitochondria and the ER and promotes cell metabolic activity (PubMed : 18650243, PubMed : 32225006). Also activates the ERK1/2 signaling pathway to promote cell migration and wound closure (PubMed : 18650243). In contrast with Hst 1, not able to promote cell-substrate and cell-cell adhesion (PubMed : 25903106).