Cephaeline promotes ferroptosis by targeting NRF2 to exert anti-lung cancer efficacy

Abstract

Context

Cephaeline is a natural product isolated from ipecac (Cephaelis ipecacuanha [Brot.] A. Rich. [Rubiaceae]). It exhibits promising anti-lung cancer activity and ferroptosis induction may be a key mechanism for its anti-lung cancer effect.

Objectives

This study investigates the anti-lung cancer activity and mechanisms of cephaeline both in vitro and in vivo.

Materials and methods

H460 and A549 lung cancer cells were used. The cephaeline inhibition rate on lung cancer cells was detected via a Cell Counting Kit-8 assay after treatment with cephaeline for 24 h. Subsequently, the concentrations of 25, 50 and 100 nM were used for in vitro experiments. In addition, the antitumour effects of cephaeline (5, 10 mg/kg) in vivo were evaluated after 12 d of cephaeline treatment.

Results

Cephaeline showed significant inhibitory effects on lung cancer cells, and the IC₅₀ of cephaeline on H460 and A549 at 24, 48 and 72 h were 88, 58 and 35 nM, respectively, for H460 cells and 89, 65 and 43 nM, respectively, for A549 cells. Meanwhile, we demonstrated that ferroptosis is the key mechanism of cephaeline against lung cancer. Finally, we found that cephaeline induced ferroptosis in lung cancer cells by targeting NRF2.

Discussion and conclusion

We demonstrated for the first time that cephaeline inhibits NRF2, leading to ferroptosis in lung cancer cells. These findings may contribute to the development of innovative therapeutics for lung cancer.

Keywords:

• Natural products
• ipecac
• GPX4
• SLC7A11
• TBHQ

Author contributions

L.Z. and P. C. conceived the idea, analysed data, wrote the manuscript; Q. Y., S.L. and P. C. jointly performed the experiments.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

This study was supported by National Natural Science Foundation of China (82204689) and Scientific Research Foundation of Hangzhou City University (Z2022066).