HLA-F is a non-classical MHC class I molecule functioning in two distinct forms: a peptide-bound heterotrimeric complex with β2-microglobulin that presents post-translationally modified self-peptides [UniProt], and a peptide-free open conformer (OC) lacking peptide and β2-microglobulin [UniProt]. The peptide-bound form acts as a ligand for the inhibitory receptor LILRB1, contributing to maternal-fetal immune tolerance [UniProt]. The peptide-free OC engages activating KIR3DS1 receptors on NK cells, triggering degranulation and anti-viral cytokine production [UniProt], while simultaneously interacting with inhibitory KIR3DL2 receptors to suppress NK and T cell effector functions [UniProt]. HLA-F may cross-present exogenous antigens to CD8+ T cells and protect motor neurons through KIR3DL2 interactions [UniProt]. Clinically, reduced HLA-F expression at the maternal-fetal interface is associated with preeclampsia pathogenesis 1, while HLA-F overexpression in trophoblasts promotes cell proliferation and invasion, and increases immunoregulatory cytokine secretion in NK cells 1. In cancer, HLA-F expression correlates with poor prognosis in gastric cancer, independently affecting postoperative outcomes 2. HLA-F polymorphisms show associations with HBV infection outcome 3, malaria susceptibility 4, and coronary artery disease risk 5, suggesting broader roles in infectious disease and inflammatory pathologies.