Table 2.

Mechanisms of lactoferrin in indirectly regulating bone metabolism.

Pathway of action	Mechanism of action (detailed description)	Key factors/pathways	Effect on bone metabolism	Key references
Skeletal Muscle Regulation	1. Lactoferrin activates the ERK signaling pathway in skeletal muscle satellite cells, inducing the assembly of the Cyclin D and CDK4 complex.	ERK → Cyclin D/CDK4	Promotes the transition of satellite cells from the G1 to the S phase, enhancing their proliferation and skeletal muscle regeneration capacity. This increases the secretion of muscle-derived myokines, which indirectly promote osteogenesis.	(6, 50, 51)
	2. By promoting skeletal muscle regeneration and function, lactoferrin increases the secretion of the myokine Irisin.	Irisin → Wnt/β-catenin, p38MAPK/ERK	Irisin promotes the differentiation of osteoblast precursors into osteoblasts and enhances their mineralization capacity by activating the Wnt/β-catenin and p38MAPK/ERK pathways, while simultaneously inhibiting bone resorption.	(49)
Energy Metabolism Regulation	1. Lactoferrin downregulates the Ca2+ and cAMP signaling pathways in intestinal cells, thereby enhancing the function of the sodium-dependent glucose transporter (SGLT1).	Ca2+/cAMP → SGLT1; PPARγ	Promotes glucose transport into intestinal epithelial cells, exerting a hypoglycemic effect. It also enhances insulin signaling via a PPARγ-dependent cascade, improving the overall metabolic environment to support osteoblast function.	(7, 55, 56)
	2. Leveraging its sugar-binding properties, lactoferrin directly binds to glucose in the gut via hydrogen bonds and van der Waals forces.	Hydrogen bonds/van der Waals forces	Modulates free sugar levels in the intestine, contributing to the maintenance of blood glucose stability, which indirectly provides a stable physiological environment for bone metabolism.	(57)
	3. Lactoferrin inhibits the activation of the hypothalamic-pituitary-adrenal (HPA) axis, reducing corticosterone levels.	Inhibition of corticosterone axis	Ameliorates insulin resistance induced by high corticosterone levels, indirectly promoting bone formation.	(58)
	4. Lactoferrin upregulates the levels of Glucagon-like peptide-1 (GLP-1).	GLP-1 → Insulin	Stimulates insulin secretion, helping to maintain blood glucose stability. Insulin promotes glucose uptake and utilization by osteoblasts in a dose-dependent manner, thereby supporting their differentiation and function.	(59, 60)
Gut Microbiota Regulation	1. Lactoferrin promotes the proliferation of intestinal epithelial cells by activating the PI3K/Akt signaling pathway.	PI3K/Akt pathway	Increases the number of mature intestinal epithelial cells, expanding the nutrient absorption area and improving the growth environment for gut microbiota, which indirectly influences bone metabolism.	(8)
	2. Lactoferrin increases the proportion of beneficial bacteria (e.g., Bifidobacterium, Lactobacillus) and decreases pathogenic bacteria (e.g., Salmonella, E. coli).	Probiotics (e.g., Bifidobacterium, Lactobacillus)	Alters the gut microbial composition, leading to a downregulation of the RANKL/OPG ratio to attenuate osteoclast activation, and an upregulation of pro-osteogenic genes like *Bmp-2* and Sparc, collectively promoting bone formation.	(66, 68–70)
	3. Lactoferrin modulates gut microbiota to reduce the production of serotonin (5-HT) from tryptophan metabolites.	Inhibition of 5-HT production	Avoids the negative regulation of bone mass by 5-HT, thereby benefiting bone mass maintenance.	(67)
Calcium-Phosphorus Metabolism Regulation	1. Utilizing its mineral-binding properties, lactoferrin forms stable, soluble complexes with calcium (Ca2+) and phosphate (PO4 3−) ions in the intestine.	Lactoferrin-mineral complex	Improves the solubility and absorption rate of minerals in the gut, providing a more sufficient supply of raw materials for bone mineralization.	(71)
	2. During fracture healing, lactoferrin enhances the function of osteoblasts.	Enhanced osteoblast function	Promotes new bone formation and mineralization, leading to a shorter fracture healing time and improved bone microstructure (e.g., increased trabecular number and thickness).	(72, 73)