Quercetin attenuates peritoneal fibrosis by upregulating ferroptosis-related glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in MeT-5A and rat models: Supported by clinical mRNA expression data
Shaxi Ouyang, Yu Chen, Siyuan Yan, Xiangyi Li, Yunling Liu, Yuling Xiao, Guoli Li, Zangyue Sun, Xiaofang HuBackground
Peritoneal fibrosis (PF) limits the long-term use of peritoneal dialysis (PD), with effective therapies lacking. Ferroptosis, an iron-dependent cell death process, has been implicated in organ fibrosis, but its role in PD-related PF remains unexplored. Quercetin, a natural flavonoid, possesses potential anti-fibrotic and anti-ferroptotic properties.
Methods
PD effluent cells from patients with different dialysis durations were analyzed for the expression of fibrosis markers (α-smooth muscle actin and collagen I) and ferroptosis-related markers (glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11)). In vitro, human peritoneal mesothelial cells (MeT-5A) exposed to high glucose were treated with quercetin to examine its effects on mitochondrial ultrastructure and marker expression. A rat model of PF was established through daily intraperitoneal injection of high-glucose dialysate, with or without quercetin administration, to evaluate histological and molecular changes in the parietal peritoneum.
Results
Prolonged dialysis duration was associated with upregulated fibrotic markers and downregulated ferroptosis-related genes in patient samples. In vitro, high glucose induced mitochondrial damage and a profibrotic phenotype in MeT-5A cells, which were significantly attenuated by quercetin. Quercetin restored the expression of GPX4 and SLC7A11, comparable to the effects of the ferroptosis inhibitor ferrostatin-1. In vivo, quercetin treatment markedly alleviated high-glucose-induced peritoneal thickening and fibrosis while enhancing the expression of ferroptosis suppressors.
Conclusion
Our findings demonstrate that ferroptosis contributes to the pathogenesis of PD-associated PF. Quercetin mitigates fibrotic progression by modulating ferroptosis, highlighting its promise as a novel therapeutic agent for preventing or treating this complication.