The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis

Abstract

BACKGROUND

Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis.

METHODS

Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining.

RESULTS

At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells.

CONCLUSION

The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.

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Acknowledgement

This study was supported by the National Research Foundation of Korea (2017R1A2B3005842 and 2019M3A9H1103651).

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Correspondence to Ok Hee Jeon or Byung‐Soo Kim.

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Go, S., Kang, M., Kwon, S.P. et al. The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis. Tissue Eng Regen Med (2021). https://doi.org/10.1007/s13770-021-00346-z

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Keywords

  • Cellular senescence
  • Ferroptosis
  • JQ1
  • Senolytic drug