Mesenchymal stem cells overexpressing CYP46A1 inhibit lipopolysaccharide-induced lipid accumulation and neuroinflammation in N9 microglial cells

Yiming Shao; Baodong Ma; Ranran Jin; Ning Kong; Jixiang Tang; Ruibo Li; Yueyao Ban; Shoukui Hu; Hui Zhang

doi:10.1016/j.ejphar.2025.177889

Mesenchymal stem cells overexpressing CYP46A1 inhibit lipopolysaccharide-induced lipid accumulation and neuroinflammation in N9 microglial cells

Eur J Pharmacol. 2025 Jul 1:177889. doi: 10.1016/j.ejphar.2025.177889. Online ahead of print.

Authors

Yiming Shao¹, Baodong Ma¹, Ranran Jin¹, Ning Kong², Jixiang Tang², Ruibo Li², Yueyao Ban², Shoukui Hu³, Hui Zhang⁴

Affiliations

¹ Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China; Department of Laboratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
² Department of Neurosurgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
³ Center of Stem Cell and Regenerative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China; Department of Laboratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China. Electronic address: shoukuihu@163.com.
⁴ Department of Neurosurgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China. Electronic address: 528zhanghui@sina.com.

PMID: 40609611
DOI: 10.1016/j.ejphar.2025.177889

Abstract

In this study, we investigated the effects of cytochrome P450 46A1 (CYP46A1)-overexpressing mesenchymal stem cells (MSCs) on neuroinflammation and lipid metabolism in N9 microglial cells. Secretory proteomic analysis of CYP46A1-MSCs revealed 261 upregulated and 87 downregulated proteins, with involvement in pathways related to neurodegenerative diseases and cholesterol metabolism. Compared with control MSCs, CYP46A1-MSCs significantly inhibited the lipopolysaccharide-induced decrease in cell viability, nitric oxide production, and release of pro-inflammatory factors in N9 microglial cells. Furthermore, CYP46A1-MSCs reduced lipid droplet formation and the accumulation of cholesterol and triglycerides in lipopolysaccharide-stimulated microglial cells. Lipidomics analysis revealed that the differentially expressed lipids primarily included sphingolipids, glycerolipids, sterol lipids, and glycerophospholipids. Additionally, CYP46A1-MSCs reversed the LPS-induced changes in the expression of glycerophospholipid-metabolizing enzymes, including diacylglycerol kinase γ (Dgkg), glycerol-3-phosphate acyltransferase 3 (Gpat3), phosphatidate phosphatase (Lpin1), and phospholipid phosphatase 3 (Plpp3). These findings suggest that CYP46A1-MSCs have a potent anti-inflammatory effect and can modulate lipid metabolism in microglia, highlighting their potential as a therapeutic strategy for neuroinflammatory diseases.

Keywords: CYP46A1; lipid metabolism; lipidomics; mesenchymal stem cell; neuroinflammation; proteomics.