Investigation of Mechanism of Simiaowan in Promoting Intestinal Uric Acid Excretion in Hyperuricemic Rats by Inhibiting Ferroptosis of Intestinal Epithelial Cells via SLC7A11/GPX4 Signaling Pathway
10.13422/j.cnki.syfjx.20260461
- VernacularTitle:基于SLC7A11/GPX4信号通路探究四妙丸抑制肠上皮细胞铁死亡促进高尿酸血症大鼠肠道尿酸排泄的作用机制
- Author:
Zhongyou ZHANG
1
;
Huilin FENG
1
;
Lian DUAN
1
;
Xuping FAN
1
;
Shaoang DONG
1
;
Lingchun WANG
1
;
Bowen YE
1
;
Hao DAI
1
Author Information
1. Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine（TCM），Shanghai 200052，China
- Publication Type:Journal Article
- Keywords:
Simiao Wan;
hyperuricemia;
intestinal uric acid excretion;
solute carrier family 7 member 11/glutathione peroxidase 4 （SLC7A11/GPX4） signaling pathway;
ferroptosis;
adenosine triphosphate-binding cassette transporter G2 （ABCG2）
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2026;32(18):151-161
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the mechanism by which Simiao Wan improve intestinal uric acid excretion in hyperuricemic （HUA） rats by inhibiting ferroptosis via the solute carrier family 7 member 11/glutathione peroxidase 4 （SLC7A11/GPX4） signaling pathway. MethodsForty-eight male SD rats were randomly assigned to a normal group， a model group， a low-dose Simiao Wan group （282.6 mg·kg-1）， a high-dose Simiao Wan group （565.2 mg·kg-1）， an etoricoxib group （5.4 mg·kg-1）， and a ferroptosis inhibitor （Fer-1） group （2 mg·kg-1）. Except for the normal group， rats in all other groups were intraperitoneally injected with potassium oxonate （100 mg·kg-1） combined with intragastric administration of hypoxanthine （500 mg·kg-1） to establish the HUA rat model. After 21 days， rats in each administration group received the corresponding dose of drug by gavage， rats in the Fer-1 group received intraperitoneal injection of Fer-1， and rats in the normal and model groups were given an equal volume of normal saline by gavage. After sampling， serum levels of uric acid （SUA）， creatinine （Cr）， and blood urea nitrogen （BUN） were measured using biochemical assays. The content of ferrous ion （Fe2+）， reduced glutathione （GSH）， and malondialdehyde （MDA）， as well as superoxide dismutase （SOD） activity in ileal tissues were determined. Hematoxylin and eosin （HE） staining was performed to observe the histopathological changes in the ileum， and transmission electron microscopy was used to observe mitochondrial alterations in the ileal tissue. Immunohistochemistry （IHC） and Western blot were used to detect the protein expression levels of GPX4， ferritin heavy chain 1 （FTH1）， acyl-CoA synthetase long-chain family member 4 （ACSL4）， SLC7A11， and ATP-binding cassette transporter G2 （ABCG2） in ileal tissue. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to determine the mRNA expression of GPX4， FTH1， ACSL4， SLC7A11， and ABCG2 in the ileal tissue. ResultsCompared with the normal group， the model group exhibited significantly elevated serum UA， Cr， and BUN levels （P<0.01）， significantly increased content of MDA and Fe2+ in ileal tissue， and significantly decreased GSH content and SOD activity （P<0.01）. HE staining showed extensive shedding of the ileal villous epithelium， disrupted and disorganized villous structure， and incomplete local tissue architecture. Transmission electron microscopy revealed reduced mitochondrial volume， decreased or even vanished cristae， indicating ultrastructural features characteristic of ferroptosis. Molecular and immunohistochemical results demonstrated that the protein and mRNA expression levels of GPX4， FTH1， SLC7A11， and ABCG2 were significantly downregulated， whereas those of ACSL4 were significantly upregulated （P<0.05， P<0.01）. Compared with the model group， after intervention with Simiao Wan， the serum UA， Cr， and BUN levels significantly decreased in all dose groups （P<0.05，P<0.01）， the MDA and Fe2+ content in ileal tissues were significantly reduced （P<0.01）， and the GSH content and SOD activity significantly increased （P<0.01）. HE staining showed that the shedding of ileal villous epithelium was markedly alleviated， the villous structure became relatively intact and regularly arranged， and local tissue damage was obviously improved. Transmission electron microscopy showed attenuated mitochondrial damage， improvement in mitochondrial shrinkage， and partial restoration of mitochondrial cristae. Molecular and immunohistochemical results showed that Simiao Wan upregulated GPX4， FTH1， SLC7A11， and ABCG2， and downregulated ACSL4 in a dose-dependent manner. In the high‑dose group， all indices improved significantly （P<0.05，P<0.01）， whereas in the low‑dose group， only improving trends were observed for FTH1， SLC7A11 mRNA， and ABCG2 protein. ConclusionSimiao Wan may inhibit ferroptosis of ileal epithelial cells by regulating the SLC7A11/GPX4 signaling pathway， and upregulate the expression of the uric acid transporter ABCG2， thereby promoting intestinal uric acid excretion and improving HUA.
