**Background:** Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein of the transferrin family, present in human exocrine fluids (e.g., breast milk at ~2.6 mg/mL, colostrum at 5.3 ± 1.9 mg/mL), neutrophil secondary granules (3–15 µg/10⁶ neutrophils), and plasma (0.2–1.5 µg/mL). Its structure comprises two lobes (N and C) that reversibly bind ferric iron with extremely high affinity (Kd ~10⁻²⁰ to 10⁻²² mol/L). The highly basic N-terminus (isoelectric point 8.5–9.0) enables binding to negatively charged surfaces of pathogens and host cells. Proteolytic cleavage by pepsin generates lactoferricin (LFC), a 25-residue peptide from bovine LF (bLFC) or a 49-residue peptide from human LF (hLFC), which adopt amphipathic conformations distinct from the parent protein.
**Methods:** This narrative review synthesizes in vitro, in vivo, and clinical trial data on LF and LFC. It covers structural biology, receptor interactions (LRP-1, CXCR4, intelectin-1, CD14, TLR2/4, DC-SIGN, nucleolin, HSPGs), and functional studies across bacterial, viral, fungal, parasitic, and cancer models. Clinical trials are summarized from published literature.
**Key Results:** LF exerts bacteriostatic effects via iron sequestration (reversible by iron supplementation) and bactericidal effects via LPS binding and membrane destabilization. LF inhibits biofilm formation in Pseudomonas aeruginosa at fivefold lower concentrations than needed for bacteriostasis. LFCs act directly on microbial membranes, with bLFC more potent than hLFC. LF binds plasminogen via its cationic N-terminus and reduces its proteolytic activity; LFC but not full-length LF blocks both plasminogen conversion and intrinsic plasmin activity, as well as TMPRSS2. Against SARS-CoV-2, LF acts through multiple mechanisms: blocking S protein–HSPG interaction, direct S protein binding, TMPRSS2 blockade (LFC only), cathepsin L inhibition, IFN response enhancement, RdRp inhibition, and iron homeostasis maintenance. LF immunomodulation includes competing with LBP for LPS binding, preventing LPS–CD14 interaction, downregulating TLR4 expression, and reducing proinflammatory cytokines (TNF-α, IL-6, IL-1β). LF also suppresses NET release and promotes DC maturation toward Th1 responses. In mouse models, LF treatment reduced serum TNF-α, IL-6, IL-10, and NO in endotoxemia, and protected against LPS- and E. coli-induced intestinal injury. LF knockout mice show increased susceptibility to inflammatory disorders. Antitumor activities include G1/S cell-cycle arrest, apoptosis induction, angiogenesis inhibition via TRAF6/NF-κB/HIF-1α/VEGF-A suppression, and EMT reversal. Clinical trials show oral bLF reduces diarrhea prevalence and severity in toddlers, improves H. pylori eradication when added to standard therapy, and may reduce colorectal polyp growth with increased NK cell activity. In COVID-19, two small Italian studies suggested faster viral clearance and symptom reduction with bLF, but a double-blind RCT in healthcare workers found no prevention benefit, and a pilot study in Egypt showed no significant differences in recovery.
**Clinical Implications:** LF and LFC represent promising natural compounds for infection and inflammation management, with potential applications in neonatal sepsis, diarrheal disease, H. pylori infection, periodontitis, respiratory infections, iron deficiency anemia, and COVID-19. However, clinical evidence remains mixed, with some trials showing no benefit in well-nourished populations. The European Food Safety Authority (2012) and FDA (2014, GRN 465) recognize bLF as generally safe as a food supplement. Larger randomized controlled trials with standardized dosing, timing, and duration are needed to establish therapeutic roles, particularly for COVID-19. LF-conjugated nanoparticles for targeted cancer drug delivery represent an emerging application.