Lycopene prevents the intestinal toxicity caused by cyclophosphamide via NCOA4-induced ferroptosis pathway

Abstract

This study evaluated the novel mechanism of lycopene (LP) preventing cyclophosphamide (CYC)-induced intestinal toxicity. The results of in vitro showed that compared with the control, phosphoramide mustard (PM) treatment significantly reduced Caco-2 cell viability and SOD activity, increased MDA content, promoted Fe2+ accumulation, and upregulated NCOA4. Compared with the PM treatment, Fer-1 + PM or siRNA-NCOA4 + PM significantly increased GSH content in Caco-2 cells, decreased ROS content, inhibited autophagy, downregulated NCOA4 and COX2, and upregulated GPX4 and FTH1. More importantly, PM + 8 μM LP significantly reversed these effects of PM. The results of in vivo showed that compared with the control, the autophagy in the intestinal tissues of CYC mice was significantly increased, and the NCOA4 and COX2 proteins were up-regulated, while the GPX4 and FTH1 were down-regulated. Compared with the CYC group, 10 mg/kg LP + CYC significantly reversed the above phenomenon. In conclusion, LP inhibited CYC-induced ferroptosis by blocking the NCOA4-mediated ferritinophagy signaling pathway.

Keywords

• Lycopene
• Cyclophosphamide
• Phosphoramide mustard
• Intestinal toxicity
• Ferroptosis