Transcription Factor SREBF1 Regulating the Expression of Lipid Metabolism Gene FADS1 Participates in Lupus Nephritis Glomerular Mesangial Cell Injury

Background: Mesangial cells (MCs) injury is a key feature of lupus nephritis (LN). Elevated lipid levels were associated with LN prognosis in previous reports; however, the association between MCs and lipid metabolism remains unclear. This study aims to identify lipid metabolism–related transcription factors (TFs) and their target genes in MC injury in LN. Methods: Correlations between LN clinical and renal pathological indicators were evaluated. Public single-cell RNA sequencing data from LN mouse kidneys were analyzed to identify lipid metabolism–related regulons, TFs, and their downstream target genes in the MCs cluster. TF–target gene expression and physical interaction were validated by immunohistochemistry and chromatin immunoprecipitation–qPCR (ChIP–qPCR). In vitro and in vivo experiments were conducted to examine their roles in MCs inflammation and proliferation. Results: Clinical and renal pathological data of 289 LN patients indicated that elevated lipid levels are positively correlated with MCs proliferation. The most upregulated regulon, Srebf1(+), and its downstream lipid metabolism–related gene, Fads1, were identified. SREBF1 directly bound to the FADS1 promoter. Both SREBF1 and FADS1 were upregulated in LN models. Inhibition of SREBF1 improved lipid metabolism and reduced MCs injury. FADS1 overexpression confirmed the contribution of the SREBF1/FADS1 axis to inflammation and proliferation. Moreover, supernatants from M1 macrophages increased SREBF1 expression in MCs, highlighting macrophage-MC crosstalk in lipid-inflammatory regulation. Conclusion: In LN, elevated lipid levels are positively correlated with MCs proliferation. The lipid metabolism–related SREBF1/FADS1 contributes to MCs injury, and its inhibition may alleviate MCs inflammation and proliferation. Funding: Government Support – Non-U.S.Flowchart overview of this study