Fuzheng Nizeng Decoction regulated ferroptosis and endoplasmic reticulum stress in the treatment of gastric precancerous lesions: A mechanistic study based on metabolomics coupled with transcriptomics

Abstract

Background: Fuzheng Nizeng Decoction (FZNZ) has a history of decades in gastric precancerous lesions (GPL) treatment, which has shown clear clinical efficacy. Blocking GPL is a key measure to reduce the incidence of gastric cancer (GC). Therefore, we aim to investigate the mechanism of FZNZ-induced ferroptosis and endoplasmic reticulum (ER) in MNNG-induced gastric precancerous lesion (MC) cells, which has been rarely studied in Traditional Chinese Medicine (TCM).Methods: First, CCK8 and lactate dehydrogenase assays were conducted to study the potential effect of FZNZ on MC cells. Second, combined transcriptomic and metabolomic analysis were used to explore the effect and mechanism of FZNZ. Functionally, the occurrence of ferroptosis was assessed by transmission electron microscopy morphological observation and measurement of ferrous iron levels, lipid peroxidation, and glutathione levels. Finally, the expression levels of mRNAs or proteins related to ferroptosis and ER stress were determined by qPCR or western blot assays, respectively.Results: FZNZ inhibited MC cells viability and induced cell death. By metabolomics coupled with transcriptomics analysis, we found that the mechanism of FZNZ treatment induced ferroptosis and was related to glutathione metabolism and ER stress. We then, for the first time, found that FZNZ induced ferroptosis, which contributed to an increase in intracellular ferrous iron, reactive oxygen species, and malondialdehyde and a decrease in glutathione. Meanwhile, the protein level of glutathione peroxidase 4 (GPX4) was decreased. The mRNA levels of ATF3/CHOP/CHAC1, which are related to ferroptosis and ER stress, were also upregulated.Conclusion: Our results elaborate that FZNZ could induce ferroptosis and ER stress in MC cells, and reduce GPX4/GSH. ATF3/CHOP/CHAC1 may play a crosstalk role, which provides a new molecular mechanism for the treatment of GPL.

Network pharmacology, bioinformatics, and experimental validation to identify the role of Hedyotis diffusa willd against gastric cancer through the activation of the endoplasmic reticulum stress

“…Studies have found that herbal medicine for GC may be associated with ER stress pathway activation [ 15 , 35 ]. Ferroptosis and ER stress could be brought on by Fuzheng Nizeng Decoction [ 36 ]. Small molecules from traditional Chinese medicine are able to activate ER stress to exert anti-tumor effects.…”

High Hepcidin Levels Promote Abnormal Iron Metabolism and Ferroptosis in Chronic Atrophic Gastritis

“…Ferroptosis is a distinct form of cell death that relies on iron-dependent lipid peroxidation, distinguishing it from apoptosis, autophagy, and necrosis [ 16 ]. Ferroptosis has been observed in both inflammatory bowel disease (IBD) and GC [ 25 , 26 ]. The antitumor effects of ferroptosis have been demonstrated, but it can also promote tumor growth and survival [ 27 ].…”

Jian Yun Qing Hua Decoction inhibits malignant behaviors of gastric carcinoma cells via COL12A1 mediated ferroptosis signal pathway

“…As revealed by IHC assay, JYQHD group displayed the reduced levels of COL12A1, GPX4 and SLC7A11, while an elevated levels of COL12A1, GPX4 and SLC7A11 were shown in JYQHD + oe-COL12A1 group. A previous study elaborated that Fuzheng Nizeng Decoction regulated ferroptosis and endoplasmic reticulum stress in the treatment of gastric precancerous lesions [ 84 ]. Our consequences presented that JYQHD activated the ferroptosis and inhibited the stemness in GC cell lines.…”