Mechanism of Emodin on Ferroptosis by Interfering PI3K/Akt/mTOR Signaling Pathway in Rats with Precancerous Lesions of Liver Cancer
Objective To explore the regulatory effects of emodin on the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of ra-pamycin(mTOR)signaling pathway in diethylnitrosamine(DEN)induced precancerous lesions of liver cancer of rats and its impacts on ferroptosis.Methods Modeling of precancerous lesions of liver cancer was carried out by DEN inducing precancerous lesions of liver cancer on rats.A total of 50 male SD rats were randomly divided into control group[no mod-eling+10 ml/(kg·d)normal saline by gavage],DEN model group[precancerous lesions of liver cancer modeling+10 ml/(kg·d)normal saline by gavage],DEN+emodin group[precancerous lesions of liver cancer modeling+80 mg/(kg·d)emodin concentrated solution by gavage],DEN+liver-protecting tablet group[precancerous lesions of liver canc-er modeling+900 mg/kg liver-protecting tablet by gavage]and DEN+emodin+liver-protecting tablet group[precan-cerous lesions of liver cancer modeling+80mg/(kg·d)emodin concentrated solution by gavage+900 mg/kg liver-pro-tecting tablet by gavage],with 10 rats in each.The rats in each group were treated continuously for 12 weeks.Serum ala-nine aminotransferase(ALT),aspartate aminotransferase(AST)and albumin(ALB)levels of rats in each group were detected by biochemical analysis;the liver indexes of rats in each group was compared.The levels of serum interleukin 1 beta(IL-1β),tumor necrosis factor alpha(TNF-α)and IL-10 contents of rats in each group were detected by enzyme-linked immunosorbent assay(ELISA).The pathological changes of liver tissues were observed by hematoxylin-eosin(HE)staining;the apoptosis of liver tissue cells was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling(TUNEL).The protein expression of glutathione peroxidase 4(GPX4),a central regulator of ferropto-sis,in liver tissues of rats in each group was detected by immunohistochemistry.The pathological changes in liver tissues of rats in each group were analyzed by Masson's trichrome staining(MASSON).The mRNA levels of PIK3,Akt and mTOR in liver tissues of rats in each group was detected by reverse transcription polymerase chain reaction(RT-PCR).Results Compared with the control group,ALT level,AST level and liver indexes of the rats in the DEN model group significantly increased,and ALB level significantly decreased(all P＜0.05),the serum IL-1β,TNF-α and IL-10 contents significantly increased(all P＜0.05);obvious inflammatory infiltration of hepatocytes,increased cellular immune re-sponse,morphological distortion of hepatocytes and degeneration and death of hepatocytes in liver tissues were occured;the protein expression of GPX4 significantly decreased(P＜0.05),the mRNA expressions of PI3K,Akt and mTOR sig-nificantly increased(all P＜0.05).Compared with the rats in DEN model group,ALT levels,AST levels and liver inde-xes in DEN+emodin group,DEN+liver-protecting tablet group and DEN+emodin+liver-protecting tablet group signifi-cantly decreased,while ALB significantly increased(all P＜0.05),the contents of serum IL-1β,TNF-α and IL-10 signifi-cantly decreased(all P＜0.05);the arrangement of liver cells tended to be normal,the inflammatory infiltration reduced,the diffuse fibrosis of liver cells weakened,the morphology of liver cells around blood vessels and bile ducts gradually im-proved and the blue collagen fiber tissue reduced;the protein expression of GPX4 in liver tissues significantly increased(all P＜0.05),the mRNA expressions of PI3K,Akt and mTOR significantly decreased(all P＜0.05),and the improve-ment effect of DEN+emodin+liver-protecting tablet group was obviously better than that of DEN+emodin group and DEN+liver-protecting tablet group(all P＜0.05).Conclusion Emodin can improve rat precancerous lesions of liver cancer by promoting the expression of ferroptosis-related proteins GPX4,and its mechanism may be related to the regula-tion of PI3K/Akt/mTOR signaling pathway by emodin.
EmodinPrecancerous lesions of liver cancerPhosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathwayFerroptosis
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