JAK2/STAT3 Signaling Pathway and Klotho Gene in Cadmium-induced Neurotoxicity In Vitro and In Vivo

Biol Trace Elem Res. 2023 Jun;201(6):2854-2863. doi: 10.1007/s12011-022-03370-9. Epub 2022 Sep 27.


Cadmium (Cd), a common heavy metal in the environment, is associated with cognitive impairment. In the present study, we carried out a preliminary inquiry to explore whether Cd causes neurotoxicity by regulating the JAK2/STAT3 signaling pathway and affecting the expression of klotho genes in vivo and in vitro, providing clues for the mechanism of Cd-induced cognitive dysfunction. The rat samples were injected with Cd chloride solution for 14 weeks, and the memory function of the rats was detected. Different concentrations of Cd and JAK2/STAT3 signaling pathway inhibitors were used to treat PC12 cells and thus detect the apoptosis rate. The protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3, and klotho in rat and PC12 cell were detected by ELISA and Western blot, respectively. With the increase in exposure dose, the memory function of rats was severely impaired. The expression of p-JAK2 and p-STAT3 proteins was significantly up-regulated, whereas that of klotho was significantly down-regulated both in vivo and in vitro (p < 0.05). In comparison with the high-dose Cd exposure group, after adding tyrphostin AG490 (AG490), the apoptosis rate of PC12 cells increased, whereas the phosphorylation levels of JAK2 and STAT3 in the cells decreased significantly (p < 0.05). Cd exposure may cause neurotoxicity by regulating the JAK2/STAT3 signaling pathway and down-regulating klotho protein expression, leading to cognitive dysfunction.

Keywords: Cadmium; In vitro; In vivo; JAK2/STAT3 signaling pathway; Klotho.

MeSH terms

  • Animals
  • Apoptosis
  • Cadmium* / metabolism
  • Cadmium* / toxicity
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Klotho Proteins
  • Rats
  • STAT3 Transcription Factor
  • Signal Transduction
  • Tyrphostins* / pharmacology


  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Cadmium
  • Jak2 protein, rat
  • Janus Kinase 2
  • STAT3 Transcription Factor
  • Tyrphostins
  • Stat3 protein, rat
  • Klotho Proteins