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Kaempferol inhibits osteoclast differentiation and bone resorption by targeting the TNF-α/NF-κB and SRC/PI3K/AKT

Qiting Yu1, Taiping Jiang2, Yunpeng Zhao1

  • 1Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550000, China.

Scientific Reports
|January 27, 2026
PubMed

Insights

Kaempferol effectively inhibits osteoclast differentiation and bone resorption by targeting key signaling pathways, offering a potential therapeutic strategy for osteoporosis. This study elucidates its dual action against osteoclastogenesis and oxidative stress.

Area of Science:

  • Pharmacology and Traditional Chinese Medicine
  • Molecular Biology and Biochemistry
  • Bone Biology and Osteoporosis Research

Background:

  • Osteoporosis is a significant skeletal disorder characterized by decreased bone mass and increased fracture risk.
  • Kaempferol, a natural flavonoid, shows promise in regulating osteoporosis, but its precise molecular mechanisms require detailed investigation.
  • Understanding kaempferol's targets and pathways is crucial for developing novel anti-osteoporotic therapies.

Purpose of the Study:

  • To elucidate the molecular mechanism of kaempferol's anti-osteoporotic effects using network pharmacology and experimental validation.
  • To identify key targets and signaling pathways modulated by kaempferol in the context of osteoporosis.
  • To evaluate the inhibitory effects of kaempferol on osteoclast differentiation and oxidative stress.

Main Methods:

  • Network pharmacology approach utilizing TCMSP and SwissTargetPrediction databases to identify kaempferol targets.
  • Protein-protein interaction (PPI) network analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment.
  • Experimental validation in RAW 264.7 cells, including cell viability assays, osteoclast differentiation and resorption assessments, oxidative stress marker analysis, and molecular mechanism studies (RT-qPCR, Western blotting).

Main Results:

  • Network pharmacology identified 37 core targets and highlighted kaempferol's high binding affinity with AKT, NF-κB, PI3K, SRC, and TNF-α.
  • Kaempferol significantly increased RAW 264.7 cell viability, dose-dependently inhibited osteoclast differentiation and bone resorption, and reduced oxidative stress markers (ROS, MDA) while increasing SOD activity.
  • Kaempferol downregulated osteoclastogenesis-related genes (RANK, CSF1R, c-Fos, CTSK, MMP-9) and inhibited the TNF-α/NF-κB and SRC/PI3K/AKT signaling pathways.

Conclusions:

  • Kaempferol demonstrates dual inhibitory effects on osteoclast differentiation and oxidative stress, validating its anti-osteoporotic potential.
  • The anti-resorptive activity of kaempferol is attributed to the coordinated inhibition of RANK/M-CSF signaling and downstream TNF-α/NF-κB and SRC/PI3K/AKT pathways.
  • These findings provide a comprehensive understanding of kaempferol's molecular mechanisms, supporting its development as a therapeutic agent for osteoporosis.

Keywords:
Bone resorption functionKaempferolNetwork pharmacologySRC/PI3K/AKT signaling pathwayTNF-α/NF-κB signaling pathway

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