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Background and objectives <p>Splenic immune cells are known to contribute to atherosclerotic plaque inflammation, yet the systemic metabolic crosstalk between the spleen and the atherosclerotic heart remains largely uncharacterized. This study aims to define the spleen-specific metabolic signatures of atherosclerosis using untargeted and targeted metabolomics.</p> Methods <p><i>Apoe</i><sup><i>–/–</i></sup> mice were fed a high-fat diet (HFD) for 10&#xa0;weeks (early atherosclerosis group) or 20&#xa0;weeks (advanced atherosclerosis group), with wild-type mice as controls. Body and spleen weight was measured, and the aortic arch was isolated and examined under a microscope. Spleens were then collected and processed for metabolomics analysis. Untargeted metabolomics was performed using liquid chromatography–mass spectrometry (LC–MS) to profile global metabolite changes. Data were analyzed by univariate and multivariate statistics, followed by Kyoto Encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Targeted metabolomics was subsequently conducted for precise quantification analysis of splenic oxylipins.</p> Results <p>Early and advanced plaques developed in <i>Apoe</i><sup><i>–/–</i></sup> mice at both 10 and 20&#xa0;weeks of HFD, respectively. Spleen weight was higher in the advanced atherosclerosis group. A total of 435 metabolites were significantly altered in the spleens of early atherosclerotic mice compared to controls, with 324 elevated and 111 reduced metabolites. Meanwhile, 472 metabolites were altered in the advanced group, including 321 increased and 151 decreased metabolites. KEGG analysis identified arachidonic acid metabolism as the most prominently disturbed pathway. Targeted oxylipin profiling revealed 30 differentially enriched oxylipins in early plaques and 23 in advanced plaques. Seven key oxylipins, including leukotriene B4 (LTB4), thromboxane B2 (TXB2), 5,6-EET, 11(12)-DiHET, 6-trans-12-epi-LTB4, 6-trans-LTB4, and 8,9-EET, were consistently altered at both stages of atherosclerosis.</p> Conclusions <p>Our findings reveal profound alterations in the splenic metabolome, particularly in the oxylipin profile, during atherosclerosis progression. The consistent changes of seven specific oxylipins suggest their potential role as key mediators of the spleen–atherosclerosis axis and as promising targets for further investigation.</p>

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Splenic oxylipin signatures in atherosclerosis: insights from integrated untargeted and targeted metabolomics

  • 期刊论文

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  • 发表日期：

    2026年6月2日

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  • Chunfang Zan,
  • Xinyu Zhang,
  • Lina Qi,
  • Zhifang Wu,
  • Sijin Li

摘要

Background and objectives

Splenic immune cells are known to contribute to atherosclerotic plaque inflammation, yet the systemic metabolic crosstalk between the spleen and the atherosclerotic heart remains largely uncharacterized. This study aims to define the spleen-specific metabolic signatures of atherosclerosis using untargeted and targeted metabolomics.

Methods

Apoe–/– mice were fed a high-fat diet (HFD) for 10 weeks (early atherosclerosis group) or 20 weeks (advanced atherosclerosis group), with wild-type mice as controls. Body and spleen weight was measured, and the aortic arch was isolated and examined under a microscope. Spleens were then collected and processed for metabolomics analysis. Untargeted metabolomics was performed using liquid chromatography–mass spectrometry (LC–MS) to profile global metabolite changes. Data were analyzed by univariate and multivariate statistics, followed by Kyoto Encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Targeted metabolomics was subsequently conducted for precise quantification analysis of splenic oxylipins.

Results

Early and advanced plaques developed in Apoe–/– mice at both 10 and 20 weeks of HFD, respectively. Spleen weight was higher in the advanced atherosclerosis group. A total of 435 metabolites were significantly altered in the spleens of early atherosclerotic mice compared to controls, with 324 elevated and 111 reduced metabolites. Meanwhile, 472 metabolites were altered in the advanced group, including 321 increased and 151 decreased metabolites. KEGG analysis identified arachidonic acid metabolism as the most prominently disturbed pathway. Targeted oxylipin profiling revealed 30 differentially enriched oxylipins in early plaques and 23 in advanced plaques. Seven key oxylipins, including leukotriene B4 (LTB4), thromboxane B2 (TXB2), 5,6-EET, 11(12)-DiHET, 6-trans-12-epi-LTB4, 6-trans-LTB4, and 8,9-EET, were consistently altered at both stages of atherosclerosis.

Conclusions

Our findings reveal profound alterations in the splenic metabolome, particularly in the oxylipin profile, during atherosclerosis progression. The consistent changes of seven specific oxylipins suggest their potential role as key mediators of the spleen–atherosclerosis axis and as promising targets for further investigation.