Quercetin inhibits caspase-1-dependent macrophage pyroptosis in experimental folic acid nephropathy

Xianli Gao; Caiyun Guo; Wenjun Li; Yingdong Deng; Wenjun Ning; Jiaqi Xie; Xiaoying Zhan; Youling Fan; Hongtao Chen; Zengping Huang; Jun Zhou

doi:10.1186/s13020-024-00885-2

Quercetin inhibits caspase-1-dependent macrophage pyroptosis in experimental folic acid nephropathy

Chin Med. 2024 Jan 16;19(1):11. doi: 10.1186/s13020-024-00885-2.

Authors

Xianli Gao^#^{1

2}, Caiyun Guo^#¹, Wenjun Li¹, Yingdong Deng¹, Wenjun Ning¹, Jiaqi Xie¹, Xiaoying Zhan¹, Youling Fan^{3

4}, Hongtao Chen⁵, Zengping Huang², Jun Zhou⁶

Affiliations

¹ Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
² Department of Anesthesiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
³ Department of Anesthesiology, The First People's Hospital of Kashgar, Xinjiang, China.
⁴ Department of Anesthesiology, The Second People's Hospital of Panyu, Guangzhou, China.
⁵ Department of Anesthesiology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
⁶ Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. zhoujun7843@smu.edu.cn.

^# Contributed equally.

Abstract

Background: The role of pyroptosis in kidney disease is limited and incomplete. Quercetin, a flavonoid compound present in a variety of fruits, vegetables, and plants, has shown antioxidant and anti-inflammatory properties. This study was designed to validate the importance of pyroptosis in an experimental model of folic acid nephropathy and to explore the effect of quercetin in protecting against pyroptosis.

Methods: Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were used to establish the correlation between pyroptosis and folic acid nephropathy. Immune cell infiltration, network pharmacology and single-cell RNA sequencing analysis were utilized to ascertain the specific target of quercetin in relation to pyroptosis. Finally, quercetin's role was verified in vivo and in vitro.

Results: The GSEA analysis revealed a significant correlation between pyroptosis and folic acid nephropathy (NES = 1.764, P = 0.004). The hub genes identified through WGCNA were closely associated with inflammation. Molecular docking demonstrated a strong binding affinity between quercetin and caspase-1, a protein known to be involved in macrophage function, as confirmed by immune cell infiltration and single-cell analysis. Quercetin demonstrated a significant amelioration of kidney injury and reduction in macrophage infiltration in the animal model. Furthermore, quercetin exhibited a significant inhibition of caspase-1 expression, subsequently leading to the inhibition of pro-inflammatory cytokines expression, such as IL-1β, IL-18, TNF-α, and IL-6. The inhibitory effect of quercetin on macrophage pyroptosis was also confirmed in RAW264.7 cells.

Conclusion: This study contributes substantial evidence to support the significant role of pyroptosis in the development of folic acid nephropathy, and highlights the ability of quercetin to downregulate caspase-1 in macrophages as a protective mechanism against pyroptosis.

Keywords: Caspase-1; Folic acid; Macrophage; Pyroptosis; Quercetin.

Abstract

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