(OR08-02-23) CYPOR Is a Promising Target for Lycopene Preventing Atrazine-Induced Ferroptosis in the Mouse Liver

Objectives: Atrazine (ATZ) is a widely used herbicide that has been shown to promote ferroptosis in liver, leading to the liver diseases. Lycopene (LYC) is a carotenoid with high antioxidant capacity and has an inhibitory effect on ferroptosis. Although some studies have shown that LYC can antagonize the occurrence of ATZ-induced ferroptosis in liver tissue, their specific pathways are still unknown. Therefore, the specific mechanism of LYC antagonism against ATZ-induced liver injury was investigated in this study.

Methods: Mice were randomly divided into 7 groups: Con, 5mg/kg LYC, 50mg/kg and 200mg/kg ATZ, 50mg/kg and 200mg/kg ATZ+5mg/kg LYC. In vitro experiments, AML12 were divided into 6 groups: Con, 5μM LYC, 200μM ATZ, 150μM DACT, 200μM ATZ and 150μM DACT+5μM LYC. Histopathology analysis, serum biochemical parameters and mitochondrial ultrastructure were used to assess liver injury. The qRT-PCR, western blot and immunofluorescence were used to detect liver ferroptosis-related indicators. Silencing and overexpression of CYPOR were to assess the mechanism by which LYC antagonized hepatocytes ferroptosis caused by ATR.

Results: The results indicated that ATZ caused abnormal accumulation of lipid peroxides and iron ions, blurred mitochondrial cristae, promoting larger hepatocyte spacing and disturbed hepatocyte plate arrangement by ferroptosis. LYC alleviated ferroptosis-induced liver injury and rescued damaged mitochondria. Moreover, ATZ promotes the expression of CYPOR signaling pathway-related indicators, while LYC inhibits these indicators. Finally, the vitro experiments demonstrated that ATZ promotes ferroptosis in hepatocytes through the CYPOR pathway, and LYC was able to inhibit ATZ-induced ferroptosis in hepatocytes by suppressing the CYPOR signaling pathway.

Conclusions: In conclusion, LYC alleviated hepatocytes ferroptosis induced by ATR by inhibiting the CYPOR signaling pathway. This study provides evidence for the role of LYC in ATR-induced hepatic ferroptosis and points to CYPOR as a potential target for the liver damage.

Funding Sources: Joint Guidance Project of Natural Science Foundation of Heilongjiang Province of China (No. LH2021C045).<br>*Corresponding author: Dr. Xue-Nan Li. E-mail address: lixuenan@neau.edu.cn