Recent advances in cellular effects of fluoride: an update on its signalling pathway and targeted therapeutic approaches

Mol Biol Rep. 2021 Jul;48(7):5661-5673. doi: 10.1007/s11033-021-06523-6. Epub 2021 Jul 12.


Fluoride is a natural element essential in minute quantities in human's to maintain dental and skeletal health. However, the disease fluorosis manifests itself due to excessive fluoride intake mostly through drinking water and sometimes through food. At the cellular energetics level, fluoride is a known inhibitor of glycolysis. At the tissue level, the effect of fluoride has been more pronounced in the musculoskeletal systems due to its ability to retain fluoride. Fluoride alters dentinogenesis, thereby affecting the tooth enamel formation. In bones, fluoride alters the osteogenesis by replacing calcium, thus resulting in bone deformities. In skeletal muscles, high concentration and long term exposure to fluoride causes loss of muscle proteins leading to atrophy. Although fluorosis is quite a familiar problem, the exact molecular pathway is not yet clear. Extensive research on the effects of fluoride on various organs and its toxicity was reported. Indeed, it is clear that high and chronic exposure to fluoride causes cellular apoptosis. Accordingly, in this review, we have highlighted fluoride-mediated apoptosis via two vital pathways, mitochondrial-mediated and endoplasmic reticulum stress pathways. This review also elaborates on new cellular energetic, apoptotic pathways and therapeutic strategies targeted to treat fluorosis.

Keywords: Apoptosis; Endoplasmic reticulum stress; Fluoride; Fluorosis; Mitochondrial dysfunction; Therapeutic approaches.

Publication types

  • Review

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Biomarkers
  • Cell Physiological Phenomena / drug effects*
  • Drug Development
  • Endoplasmic Reticulum Stress / drug effects
  • Fluorides / metabolism*
  • Fluorides / pharmacology
  • Fluorides / therapeutic use
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Molecular Targeted Therapy
  • Oxidants / metabolism
  • Oxidation-Reduction / drug effects
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*


  • Antioxidants
  • Biomarkers
  • Oxidants
  • Reactive Oxygen Species
  • Fluorides