Abstract
Objective
Immunometabolic dysregulation is increasingly recognized as a pivotal contributor to systemic lupus erythematosus (SLE). This study aims to identify novel circulating biomarkers within plasma exosomes that link fatty acid metabolic rewiring to SLE pathogenesis.
Methods
Plasma exosomes were isolated from patients with active SLE, inactive SLE, rheumatoid arthritis (RA) and healthy controls by ultracentrifugation. The proteomic and metabolomic profiles were characterized using liquid chromatography-mass spectrometry (LC-MS). Exosomal fibroblast activation protein (FAP) expression was validated by nanoflow cytometry, and fatty acid metabolites were confirmed by targeted metabolomics.
Results
Proteomic profiling revealed a marked enrichment of FAP in plasma exosomes from SLE patients, with the highest levels in active SLE. Nanoflow cytometry further validated that plasma exosomal FAP was specifically increased in SLE but not RA. Besides, metabolomics identified a characteristic fatty acid signature in SLE plasma exosomes, featuring increased saturated (palmitic acid, etc) and ω-6 polyunsaturated fatty acids (PUFAs) (arachidonic acid (AA), etc), alongside decreased ω-3 PUFAs (α-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), etc). Moreover, the AA/DHA and total ω-6/ω-3 ratios were significantly elevated, while the EPA/AA ratio was reduced in active SLE. Integrated omics analysis revealed the close relationship of exosomal FAP with fatty acid metabolism. Notably, exosomal FAP levels correlated positively with SLEDAI-2000 score and the pro-inflammatory fatty acid profiles (AA, total ω-6, AA/DHA ratio), but negatively with the anti-inflammatory profiles (DHA, EPA, total ω-3, EPA/AA ratio).
Conclusion
We identify plasma exosomal FAP as a novel biomarker linking fatty acid metabolic dysregulation to SLE.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13075-026-03801-1.
Keywords: Exosomes, Immunometabolism, Fatty acid metabolism, Fibroblast activation protein, Systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease characterized by loss of immune tolerance, production of abundant autoantibodies, multi-organ damage and metabolic disorder [1, 2]. The clinical management of SLE remains challenging due to the absence of specific molecular biomarkers, which complicates early diagnosis and precise assessment of disease activity [3]. Current diagnostic approaches primarily rely on serological markers, such as antinuclear antibodies and anti-dsDNA antibodies, combined with clinical evaluation. However, these methods often lack sensitivity in the early disease stage and fail to fully capture the considerable clinical heterogeneity of SLE [4, 5]. Therefore, there is a pressing need to discover novel, reliable biomarkers to facilitate early diagnosis, guide treatment, and precisely monitor disease progression.
Increasing studies have implicated exosomes have emerged as significant players in SLE pathophysiology [6]. They serve as key mediators of intercellular communication. Their lipid bilayer structure confers remarkable stability, protecting the cargos from degradation in the circulation [7, 8]. Growing evidence indicates that exosomes contribute to SLE pathogenesis by facilitating cell-to-cell communication, influencing membrane dynamics, and modulating intracellular signaling pathways [9, 10]. Notably, exosomes not only exhibit high stability but also mirror the pathophysiological state of their parent cells, making them as a promising source of biomarkers [11, 12]. Thus, a systematic molecular characterization of plasma-derived exosomes from SLE patients holds substantial potential for developing novel diagnostic tools and elucidating the underlying disease mechanisms.
Metabolic dysregulation is increasingly recognized as a pivotal contributor in SLE pathogenesis [13, 14]. SLE patients exhibit a high risk of cardiovascular diseases, such as hypertension, hyperlipidemia, and obesity, which significantly impact long-term outcomes [15]. These metabolic aberrations not only accelerate atherosclerosis, heightening cardiovascular risk in SLE [16], but also interact with immune dysregulation to affect disease progression [17, 18]. This study aims to systematically analyze the proteomic and lipidomic landscapes of plasma exosomes from SLE patients, identifying disease-specific exosomal proteins and lipid metabolites. Their combined utility as novel biomarkers for the early diagnosis and clinical assessment of SLE is also investigated. This work also seeks to provide theoretical support for uncovering new pathological mechanisms and refining clinical management strategies for SLE.
Materials and methods
Characteristics of patients and controls
This study was approved by the Medical Ethics Committee of Weifang People’s Hospital, Shandong Second Medical University. (Approval No. 2021SDL299). A total of 32 patients with SLE, 16 with rheumatoid arthritis (RA), and 12 age- and sex-matched normal controls (NC) were enrolled from Weifang People’s Hospital, Shandong Second Medical University (Suppl. Table 1). The SLE patients were stratified into two subgroups based on disease activity: an active SLE group (n = 16) and an inactive SLE group (N-SLE, n = 16). The NC group comprised 12 healthy individuals who underwent routine health examinations during the same period. Demographic and clinical characteristics of all participants were obtained from the hospital’s medical record system. Fresh plasma samples were collected from all subjects for subsequent proteomic and metabolomic analyses. Individual samples from every four participants within the same group were pooled in equal volumes to create a composite sample.
Isolation of plasma exosomes by ultracentrifugation
Plasma exosomes were isolated from freshly collected peripheral blood samples by ultracentrifugation using a Beckman Coulter ultracentrifuge. Briefly, 1 mL of plasma was diluted with 20 mL of phosphate-buffered saline (PBS) and centrifuged at 12,000 g for 30 min to remove cell debris and large vesicles. The supernatant was then ultracentrifuged at 120,000 g for 75 min at 4 °C. The pellet was resuspended in 20 mL of PBS and subjected to a second ultracentrifugation under the same conditions (120,000 g, 75 min, 4 °C) for exosomes purification. The final pellet was resuspended in 100 µL of PBS and stored at -80 °C for subsequent analysis. Exosome size distribution was characterized by nanoflow cytometry (NanoFCM, Xiamen, China). Morphology was examined using transmission electron microscopy (TEM, HITACHI, Tokyo, Japan). The presence of exosomal surface markers (e.g., CD63) was confirmed by NanoFCM.
Proteomic analysis
The proteomic analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at Shanghai OE Biotech Co., Ltd. (Shanghai, China). Briefly, isolated exosomes were transferred to low-protein-binding tubes and lysed in 300 µL of lysis buffer supplemented with 1 mM PMSF. The samples were sonicated and centrifuged at 12,000 g for 10 min at 4 °C to remove insoluble debris. For each composite sample, proteins were digested with trypsin to generate peptides, which were desalted using a SOLA™ HRP 96-well plate. Raw data were uploaded in database of GSA (Access number: PRJCA052579).
Metabolomic analysis
The metabolomic profiling was conducted by Shanghai OE Biotech Co., Ltd. (Shanghai, China). Briefly, a 150 µL aliquot of the exosome sample was processed using a solid-phase extraction (SPE) column. The eluate was dried under a gentle nitrogen stream, and then reconstituted in 300 µL pre-cooled methanol-water containing a mixed internal standard (4 µg/mL), followed by vortexing for 1 min. The mixture was sonicated in an ice-water bath for 10 min and then stored overnight at -40 °C. After centrifugation at 12,000 × g for 10 min at 4 °C, 150 µL of the supernatant was filtered through 0.22 μm organic phase syringe filter into an LC vial for LC-MS analysis. Raw data were uploaded in database of GSA (Access number: PRJCA052156).
Measurement of FAP in plasma exosomes
Plasma exosomes were isolated from patients with SLE (n = 24), RA (n = 11), and age- and sex-matched normal controls (n = 11) using ultracentrifugation described above. Demographic characteristics of all participants are summarized in Suppl. Table 2. Plasma exosomes were incubated with 1 µL of anti-human CD63 antibody (Cat. #353007, BD Bioscience, USA) and 1 µL of anti-human FAP antibody (Cat. #A24965, Abclonal, Wuhan, China) for 60 min in the dark. Following antibody incubation, the labeled exosomes were diluted with 20 mL of PBS and centrifuged at 120,000 × g for 60 min to remove unbound antibodies. The final pellet was resuspended in 100 µL of PBS, and the presence of CD63 and FAP on exosomes was analyzed using nanoflow cytometry (NanoFCM, Xiamen, China).
Measurement of free fatty acids in serum
Free fatty acids were quantified using LC-MS/MS on an AB Sciex 4500 system (USA). All chemical reagents were obtained from Tianjin Dadao Biotechnology Co., Ltd. (Tianjin, China). The mixture was vortexed for 1 min and centrifuged at 15,000 g for 15 min at 4 °C. The resulting supernatant was transferred, evaporated to dryness under a stream of nitrogen, and reconstituted in 500 µL of methanol. After vortexing for 1 min and a final centrifugation step (10,000 g, 10 min, 4 °C), the supernatant was transferred to an insert vial or a 96-well plate for analysis.
Statistical analysis
All statistical analyses were performed using GraphPad Prism software (version 10.1.2). Data were analyzed using either parametric or nonparametric tests based on homoscedasticity and normality assessments. Parametric analyses were conducted using Student’s t-test or one-way ANOVA. Nonparametric tests included the Mann-Whitney U test or the Kruskal-Wallis H test. Spearman’s rank correlation analysis was employed to evaluate the associations between exosomal FAP levels and clinical indexes. A two-tail p-value of less than 0.05 was considered statistically significant.
Results
Characterization of human plasma exosomes from different populations
Plasma exosomes from SLE, RA patients, and NC group were determined by nanoflow cytometry and transmission electron microscopy. Exosomes exhibited a classic cup-shaped morphology (Fig. 1A) with the diameter ranging from 40 to 120 nm (Fig. 1B). Notably, compared to the NC group, reduced size and concentration of plasma exosomes were observed in active SLE (SLE) but not RA, with a more pronounced decrease in inactive SLE (N-SLE) group (Fig. 1C and D). These results suggested a unique feature of plasma exosomes from SLE patients. Furthermore, nanoflow cytometry analysis revealed no significant difference regarding the number of CD63+ exosomes across the four groups (Fig. 1E and F).
Fig. 1.
General characterization of plasma exosomes from different human subjects. A Morphology of plasma exosomes observed by transmission electron microscopy (Scale bar: 500 nm). B Size distribution of plasma exosomes measured by nano-flow cytometry. C Statistical analysis of plasma exosome size across different groups (NC group, n=8; SLE group, n=6; N-SLE group, n=7; RA group, n=10). D Statistical analysis of plasma exosome particle concentration across different groups (NC group, n=8; SLE group, n=6; N-SLE group, n=7; RA group, n=10). E Nano-flow cytometry determining the proportion of CD63-positive plasma exosomes. F Difference of CD63-positive plasma exosomes proportions across the four groups (NC group, n=11; SLE group, n=16; N-SLE group, n=11; RA group, n=12). *, P < 0.05
The proteomic profile of plasma exosomes revealed SLE-specific upregulation of exosomal FAP
The proteomic analysis of plasma exosomes was performed to identify disease-specific protein profiles. Principal component analysis (PCA) revealed a disease-specific distribution of exosomal protein profiles of SLE and RA (Fig. 2A). Active and inactive SLE patients exhibited similar proteomic characteristics (Fig. 2A). A total of 598 exosomal proteins were identified (Fig. 2B). The up-regulated and down-regulated differentially expressed proteins (DEPs) (P-value < 0.05 and |FC| ≥ 1.2) in each group were shown in Fig. 2C and Suppl. File 1. Compared to the NC group, 153 DEPs were found in the active SLE group (Fig. 2D; Table 1). Among these DEPs, exosomal FAP was significantly up-regulated in both active and inactive SLE but not RA, with the highest level in active SLE (Fig. 2D-G). Therefore, a marked enrichment of FAP was confirmed in SLE plasma exosomes. In particular, exosomal FAP was elevated in SLE.
Fig. 2.
Proteomic analyses of the differential expressed protein profiles in plasma exosomes from SLE and RA patients. A Principal component analysis (PCA) showing separation among NC, SLE, N-SLE, and RA groups based on plasma exosomal proteins. B Number of identified plasma exosomal proteins in NC, SLE, N-SLE, and RA groups. C Number of differentially expressed proteins across group comparisons. D-G Volcano plots displaying abundance differences of differentially expressed proteins between groups: (D) SLE vs. NC, (E) N-SLE vs. NC, (F) RA vs. NC, (G) SLE vs. N-SLE. H Top GO enrichment terms for plasma exosomal FAP and other differentially expressed proteins in active SLE (SLE vs. NC). I Top GO enrichment terms for plasma exosomal FAP and other differentially expressed proteins in inactive SLE (N-SLE vs. NC). J-L Comparison of protein-protein interaction (PPI) networks centered on FAP between groups: (J) SLE vs. NC, (K) N-SLE vs. NC, (L) SLE vs. N-SLE
Table 1.
Differentially expressed plasma exosomal proteins in sle patients versus healthy controls
| Gene ID | Accession number | log2FC | p-value | Regulation | Expression location | Subcellular localization | Function |
|---|---|---|---|---|---|---|---|
| KPRP | Q5T749 | 8.117 | 0.004 | Up | Keratinocyteand air follicle | Cytoplasm | Promoting tissue repair; Promoting tumor progression and metastasis |
| S100A7 | P31151 | 6.607 | 0.000 | Up | Widely expressed | Cytoplasm and ECM | Promoting cell proliferation and migration；Promoting inflammatory response and immune modulation |
| FAP | Q12884 | 6.013 | 0.001 | Up | Fibroblast and CAF | Cell membrane | Promoting tissue repair；Promoting tumor progression and metastasis |
| MME | P08473 | 5.776 | 0.000 | Up | Widely expressed | Cell membrane | Promoting the hydrolysis of bioactive peptides; Promoting cell proliferation and migration |
| PSMD6 | Q15008 | 5.347 | 0.031 | Up | Widely expressed | Cytoplasm | Promoting protein degradation; Promoting cell cycle progression |
| HSP90AB1 | P08238 | 5.25 | 0.001 | Up | Widely expressed | Cytoplasm and Nucleus | Promoting protein folding; Enhancing cellular stress signaling; Promoting tumor cell proliferation |
| SNED1 | Q8TER0 | 4.11 | 0.000 | Up | Widely expressed | Cell membrane and Cytoplasm | Promoting cell adhesion, migration, and proliferation |
| FCRL5 | Q96RD9 | 4.055 | 0.009 | Up | B cell and T cell | Cell membrane | Enhancing B cell signaling and immunoregulatory function |
| VASN | Q6EMK4 | 3.905 | 0.044 | Up | Widely expressed | Cytoplasm | Promoting angiogenesis；Promoting cell proliferation |
| CPQ | Q9Y646 | 3.627 | 0.003 | Up | Widely expressed | Cytoplasm | Promoting inflammatory and antioxidant effects；Promoting amino acid metabolism |
| POSTN | Q15063 | 2.525 | 0.001 | Up | Widely expressed | ECM | Promoting cell adhesion, migration, and proliferation；Promoting inflammation and tumorigenesis |
| FTL | P02792 | 2.496 | 0.017 | Up | Widely expressed | Cytoplasm | Promoting iron metabolism |
| DCXR | Q7Z4W1 | 1.519 | 0.032 | Up | Widely expressed | Cytoplasm | Enhancing glucose metabolism |
| PSMB8 | P28062 | 1.443 | 0.026 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation |
| PSMA2 | P25787 | 1.361 | 0.049 | Up | Widely expressed | Cytoplasm | Promoting protein degradation |
| H2BC12 | O60814 | 1.342 | 0.002 | Up | Widely expressed | Nucleus | Promoting cell proliferation and differentiation |
| ATP5F1B | P06576 | 1.332 | 0.014 | Up | Widely expressed | Mitochondrion | Enhancing cellular energy metabolism |
| SFTPB | P07988 | 1.332 | 0.014 | Up | Alveolar type II cell | Cell membrane and Cytoplasm | Promoting alveolar stability |
| S100A12 | P80511 | 1.332 | 0.014 | Up | Widely expressed | Cytoplasm and Nucleus | Promoting inflammation；Promoting cell proliferation and differentiation |
| LGALS3BP | Q08380 | 1.239 | 0.033 | Up | Widely expressed | Cell membrane and Cytoplasm | Promoting cell proliferation and migratio；Inhibiting cell apoptosis |
| PSMA7 | O14818 | 1.225 | 0.019 | Up | Widely expressed | Cytoplasm | Promoting protein degradation |
| PSMB4 | P28070 | 1.122 | 0.030 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation； |
| PSMB6 | P28072 | 1.102 | 0.036 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation；Promoting cell cycle progression |
| IRAK4 | Q9NWZ3 | 1.089 | 0.000 | Up | Macrophage and Lymphocyte | Cytoplasm | Enhancing immune responses |
| PSMA6 | P60900 | 1.04 | 0.011 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation；Promoting cell cycle progression |
CAF Cancer-associated fibroblast, ECM Extracellular matrix
Functional analysis indicated that the up-regulated DEPs in active SLE are involved in distinct biological processes, including extracellular matrix (ECM) degradation, cellular metabolism, tissue repair, proteasomal degradation, cell proliferation, differentiation, and immune reactions (Table 1). 146 DEPs were observed in the inactive SLE group compared to NCs, including exosomal FAP (Fig. 2E; Table 2). Comparative analysis between active and inactive SLE identified 49 DEPs, including 27 upregulated proteins such as FAP, periostin (POSTN), CD36, KPRP, and PRDX6 (Fig. 2F; Table 3). Although exosomal FAP was significantly up-regulated in the N-SLE group, its level was markedly lower than that in the active SLE group (Fig. 2F; Table 3). This suggests exosomal FAP may be a key biomarker linked to SLE disease activity and tissue microenvironment remodeling.
Table 2.
Differentially expressed plasma exosomal proteins in N-SLE patients versus healthy controls
| Gene ID | Accession number | log2FC | p-value | Regulation | Expression location | Subcellular localization | Function |
|---|---|---|---|---|---|---|---|
| HSP90AB1 | P08238 | 7.692 | 0.000 | Up | Widely expressed | Cytoplasm and Nucleus | Promoting protein folding; Enhancing cellular stress signaling; Promoting tumor cell proliferation |
| ATP5F1B | P06576 | 6.287 | 0.000 | Up | Widely expressed | Mitochondrion | Enhancing cellular energy metabolism |
| RGN | Q15493 | 5.301 | 0.025 | Up | Widely expressed | Cytoplasm and Nucleus | Promoting signal transduction and cell proliferation；Promoting cell growth |
| PRG2 | P13727 | 4.719 | 0.022 | Up | Eosinophil and Skin | Cytoplasm and ECM | Enhancing immune responses |
| VASN | Q6EMK4 | 4.051 | 0.038 | Up | Widely expressed | ECM | Promoting angiogenesis；Promoting cell proliferation |
| FCRL5 | Q96RD9 | 3.963 | 0.009 | Up | B cell and T cell | Cell membrane | Enhancing B cell signaling and immunoregulatory function |
| FTL | P02792 | 2.385 | 0.011 | Up | Widely expressed | Cytoplasm | Promoting iron metabolism |
| SFTPB | P07988 | 2.258 | 0.046 | Up | Alveolar type II cell | Cell membrane and ECM | Promoting alveolar stability |
| CPQ | Q9Y646 | 2.199 | 0.040 | Up | Widely expressed | Cytoplasm | Promoting inflammatory response and immune modulation |
| S100A12 | P80511 | 2.015 | 0.038 | Up | Widely expressed | Cytoplasm and Nucleus | Promoting inflammation；Promoting cell proliferation and differentiation |
| MME | P08473 | 1.521 | 0.005 | Up | Widely expressed | Cell membrane | Promoting the hydrolysis of bioactive peptides; Promoting cell proliferation and migration |
| SAA2 | P0DJI9 | 1.521 | 0.005 | Up | Widely expressed | Plasma and ECM | Enhance immune responses; Promoting cell proliferation |
| FAP | Q12884 | 1.521 | 0.005 | Up | Fibroblast and CAF | Cell membrane | Promoting tissue repair；Promoting tumor progression and metastasis |
| POSTN | Q15063 | 1.437 | 0.011 | Up | Widely expressed | ECM | Promoting cell adhesion, migration and proliferation；Promoting inflammation and tumorigenesis |
| SPP2 | Q13103 | 1.08 | 0.000 | Up | Widely expressed | ECM | Promoting cell proliferation; Promoting bone formation |
| PSMB8 | P28062 | 1.013 | 0.005 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation |
| PSMB4 | P28070 | 0.937 | 0.016 | Up | Widely expressed | Cytoplasm | Promoting protein degradation；Promoting antigen presentation； |
Table 3.
Differentially expressed plasma exosomal proteins in SLE patients versus N‑SLE disease controls
| Gene ID | Accession number | log2FC | p-value | Regulation | Expression location | Subcellular localization | Function |
|---|---|---|---|---|---|---|---|
| MME | P08473 | 4.255 | 0.000 | Up | Widely expressed | Cell membrane | Promoting the hydrolysis of bioactive peptides; Promoting cell proliferation and migration |
| HEXB | P07686 | 2.5 | 0.000 | Up | Widely expressed | Lysosome | Enhancing glucose and lipid metabolism; |
| ANTXR2 | P58335 | 2.883 | 0.000 | Up | Widely expressed | Cell membrane | Enhancing cellular defense against harmful substances；Promoting cell adhesion and migration |
| ARHGDIB | P52566 | 2.655 | 0.000 | Up | Widely expressed | Cytoplasm | Inhibiting cell migration and proliferation；Promoting cytoskeletal remodeling |
| FAP | Q12884 | 4.493 | 0.001 | Up | Fibroblast and CAF | Cell membrane | Promoting tissue repair；Promoting tumor progression and metastasis |
| KPRP | Q5T749 | 6.431 | 0.006 | Up | Keratinocyteand air follicle | Cytoplasm | Promoting skin barrier function; Promoting cell proliferation and exert antioxidant effects |
| POSTN | Q15063 | 1.087 | 0.014 | Up | Widely expressed | ECM | Promoting cell adhesion, migration and proliferation；Promoting inflammation and tumorigenesis |
| PSMD6 | Q15008 | 1.659 | 0.029 | Up | Widely expressed | Cytoplasm | Promoting protein degradation; Promoting cell cycle progression |
| CD36 | P16671 | 2.38 | 0.034 | Up | Macrophage、Endothelial cell and Adipocyte | Cell membrane | Promoting the uptake of triglycerides and cholesterol; Promoting inflammatory response and immune modulation |
| PRDX6 | P30041 | 3.091 | 0.045 | Up | Widely expressed | Cell membrane and Cytoplasm | Protecting cells from oxidative stress；Promoting cell signaling |
Exosomal FAP was implicated in ECM remodeling and fatty acid metabolic dysregulation
FAP is a membrane-bound serine protease expressed on activated fibroblasts, immune cells, and cancer cells, and can be shed into the extracellular space [19]. FAP is known to promote tissue remodeling [20]. In our study, FAP was significantly upregulated in SLE plasma exosomes (Fig. 2D-G). Gene ontology (GO) enrichment analysis indicated that exosomal FAP and other DEPs are primarily involved in immune-inflammatory regulation and tissue remodeling, specifically in processes such as negative regulation of ECM disassembly and organization, cell adhesion, angiogenesis, cell cycle regulation, and fibrinolysis (Fig. 2H and I).
Protein-protein interaction (PPI) network analysis was performed to further explore the mechanistic role of FAP (Fig. 2J-L). Caveolin-1 (CAV1), a critical regulator of fatty acid uptake and metabolism, was significantly downregulated in SLE [21]. Here, we hypothesize that FAP upregulation may suppress CAV1, disrupting fatty acid transport and signaling. The coordinated upregulation of FAP and POSTN, a known activator of the mTOR/YAP pathway that modulates key fatty acid enzymes [22], suggests FAP may contribute to fatty acid metabolic dysregulation, revealing a novel aspect of its function in SLE pathogenesis.
Exosomal FAP is a specific biomarker for SLE
To assess the disease specificity of exosomal FAP, we analyzed its expression in RA patients. Proteomic analysis identified 139 DEPs in the RA group, such as SAA2, PRG2, and S100A9 (Suppl. File 1, Suppl. Table 3). Unlike SLE, exosomal FAP in RA showed no significant difference compared to the NC group (Fig. 2G). These findings collectively indicate that exosomal FAP represents not only a disease-specific biomarker for SLE but also a promising indicator for disease activity.
Metabolomic profiling reveals fatty acid dysregulation in SLE plasma exosomes
A total of 2,315 metabolites were identified in plasma exosomes from SLE patients using LC-MS/MS (Suppl. File 2). PCA showed significant metabolomic differences in active and inactive SLE (Fig. 3A). The differential metabolomic profiles of plasma exosomes in each comparison were summarized in Suppl. Tables 4–6, with the number of significantly altered metabolites in each group shown in Fig. 3B. Compared to NC group, active SLE patients exhibited a significant increase in metabolites within plasma exosomes, such as Palmitoleamide (PE) and PG, alongside marked decrease in arachidonic acid (AA) and phosphatidylcholines (PCs) including PS (Fig. 3C, Suppl. Table 4). These alterations indicate severe dysregulation of phospholipid metabolism in SLE. Notably, N-(7z,10z,13z-16z-Docosahexaenoic) Dopamine, a neuroprotective lipid messenger derived from docosahexaenoic acid (DHA) [23, 24], was significantly down-regulated in active SLE (Fig. 3C, Suppl. Table 4), suggesting a potential compromise in neuro-immune regulation and neuropsychiatric manifestations in SLE. In inactive SLE patients, plasma exosomes showed significant up-regulation of PE, AA, and anandamide (Fig. 3D, Suppl. Table 5). Comparison between active and inactive SLE revealed that specific PCs were significantly increased in active SLE, while certain phosphatidylethanolamines (PEs) were markedly decreased (Fig. 3E, Suppl. Table 6).
Fig. 3.
Metabolomic analyses of differential metabolites in plasma exosomes from SLE patients. A OPLS-DA score plots from metabolomics analysis comparing plasma exosomal profiles between: SLE vs NC, N-SLE vs NC, and SLE vs N-SLE. B Number of significantly different metabolites identified in each comparison group. C-E Heatmaps displaying significantly different metabolites between groups: (C) SLE vs NC, (D) N-SLE vs NC, (E) SLE vs N-SLE (Screening criteria: VIP ≥ 1, |FC| ≥ 1.5, and p ≤ 0.05). F-H Bubble plots: KEGG pathway enrichment analysis of differentially expressed metabolites: (F) SLE vs NC, (G) N-SLE vs NC, (H) SLE vs N-SLE
KEGG pathway enrichment analysis revealed distinct metabolic alterations across disease states. In active SLE patients, the key enriched pathways included glycerophospholipid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, cholesterol metabolism, and primary bile acid biosynthesis (Fig. 3F). In inactive SLE, AA metabolism and linoleic acid metabolism were the most significantly enriched pathways (Fig. 3G), suggesting a pivotal role for AA and its metabolic network in SLE immunometabolism. Comparative analysis between active and inactive SLE highlighted significant enrichment of unsaturated fatty acid biosynthesis and arachidonic acid metabolism pathways (Fig. 3H), underscoring the central role of fatty acid metabolic dysregulation in disease activity.
Taken together, active and inactive SLE patients share similar metabolic signatures in plasma exosomes, with dysregulated phospholipid and fatty acid metabolism being a hallmark of SLE.
Exosomal FAP correlates with SLE disease activity and fatty acid metabolic dysregulation
As indicated by our previous proteomic analysis, exosomal FAP served as both a disease-specific biomarker for SLE and a potential indicator of disease activity. Subsequently, the nanoflow cytometry showed FAP+ exosomes was significantly elevated in both the active SLE and inactive SLE groups, with a more pronounced increase observed in the active SLE group (Fig. 4A and B). In contrast, there was no statistically significant difference of FAP⁺ exosomes between RA and NC groups (Fig. 4A and C). Spearman correlation analysis revealed significant association between exosomal FAP level and key clinical parameters, namely, positive correlations with SLEDAI, anti-dsDNA antibody, white blood cell count, proteinuria, and urinary microalbumin, and a negative correlation with complement C3 levels and platelet count (Fig. 4D). These results confirm that exosomal FAP is linked to SLE disease activity and may play a regulatory role in disease progression.
Fig. 4.
Plasma exosomal FAP is elevated in SLE patients and correlates with disease activity. A-C Plasma exosomal FAP levels measured by nano-flow cytometry in the NC, SLE, N-SLE, and RA groups (NC group, n=11; SLE group, n=11; N-SLE group, n=13; RA group, n=11). D Correlation analysis of plasma exosomal FAP levels with clinical indices in SLE patients, including SLEDAI, anti-dsDNA antibody, C3, and C4 (SLEDAI, n=24; anti-dsDNA, n=12; C3, n=23; C4, n=23; CRP, n=20; ESR, n=24; WBC, n=24; PLT, n=24; IgG, n=23; PRO, n=22; mALB, n=11; β2-mg, n=11). *, P < 0.05; ****, P < 0.0001; ns, no statistical significance
Integrated proteomic and metabolomic analysis revealed that dysregulated exosomal FAP is associated with a complex metabolic network in SLE (Fig. 5A-C). In active SLE, exosomal FAP showed a positive correlation with PCs and a negative correlation with PEs (Fig. 5A). Similarly, a significant positive correlation was observed between exosomal FAP and the metabolite palmitoylethanolamide (PEA) in both active and inactive SLE (Fig. 5A and B). These integrated findings position exosomal FAP as a potential indicator of cellular activation and metabolic remodeling within the tissue microenvironment.
Fig. 5.
Serum free fatty acid metabolism is dysregulated in SLE patients and correlates with exosomal FAP. A-C Correlation plots of plasma exosomal FAP levels with differential fatty acid metabolites between groups: (A) SLE vs. NC, (B) N-SLE vs. NC, (C) SLE vs. N-SLE. D Free fatty acid detection using LC-MS/MS between NC, SLE and N-SLE groups（NC group, n=11; SLE group, n=11; N-SLE group, n=13. E Correlation analyses of exosomal FAP levels with fatty acid metabolites in SLE (n=24); *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, no statistical significance
Exosomal FAP is associated with pro-inflammatory fatty acid profile in SLE
Further analysis of plasma fatty acid metabolites revealed a pro-inflammatory metabolic profile in SLE patients characterized by elevated saturated fatty acids (palmitic acid, stearic acid) and the ω-6 polyunsaturated fatty acid AA, alongside reduced ω-3 polyunsaturated fatty acid (e.g., alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and DHA (Fig. 5D). This dysregulation was more pronounced in active SLE, evidenced by significantly increased AA/DHA and ω-6/ω-3 ratios and a decreased EPA/AA ratio (Fig. 5D). Spearman correlation analysis demonstrated that exosomal FAP levels positively correlated with pro-inflammatory lipid mediators (AA, total ω-6, myristic acid, AA/DHA, and ω-6/ω-3 ratios) and negatively correlated with anti-inflammatory mediators (DHA, EPA, total ω-3, ALA, and EPA/AA ratio) (Fig. 5E). These results suggest that FAP may act as a potential driver of lipid metabolic dysregulation in SLE.
Discussion
Exosomal FAP: A key node linking immune inflammation and tissue remodeling
Circulating extracellular vesicles (EVs) serve as stable carriers of bioactive molecules, faithfully mirroring pathological processes in SLE, including exosomal proteins and metabolites [25]. EVs are broadly classified into three main categories based on their size and biogenesis, including exosomes (30 to 150 nm) in diameter, microvesicles (100 to 1000 nm), and apoptotic bodies (500 to 5000 nm). A previous study has identified specific metabolites in serum exosomes from SLE patients, for instance, Pro-Asn-Gln-Met-Ser, C24:1 sphingolipid, and protoporphyrin IX, which serve as promising biomarkers for the diagnosis and disease activity estimation of SLE [26]. The study by Zhang N et al. has reported a specific urinary extracellular vesicle metabolic signature in lupus nephritis, such as glucosylsphingosine, PE N-methylated (PE-NMe), and PC [27]. These serum or urinary EV-derived molecular signatures offer a compelling alternative to invasive biopsies, with significant clinical implications for disease diagnosis and monitoring. Furthermore, EV-based liquid biopsies enable dynamic, real-time assessment of disease activity and therapeutic response, as EV cargo composition correlates with clinical parameters, such as disease activity scores and drug resistance markers, positioning this approach as a transformative tool for precision medicine in autoimmune disorders.
FAP localizes to focal adhesions and invadopodia, directly degrading ECM components and interacting with integrins to facilitate cell migration [28]. Our study identifies disease-specific elevation of FAP in plasma exosomes from SLE patients. Exosomal FAP acts as a disease-specific biomarker in SLE, the levels of which correlate significantly with disease activity. We firstly demonstrate that exosomal FAP is intricately linked to a pro-inflammatory lipid network, positioning it as a potential molecular node connecting immune-metabolic dysregulation in SLE. This finding extends the established role of FAP, a serine protease expressed on activated fibroblasts, beyond its known involvement in tissue fibrosis and remodeling. Beyond FAP, the proteomic landscape of SLE exosomes reveals numerous dysregulated proteins implicated in immune regulation, including POSTN, IRAK4, and PRG2.
As a serine protease predominantly expressed on activated fibroblasts [29], FAP is poised to play multifaceted roles in the pathophysiology of SLE. Current research in SLE has primarily focused on the molecular imaging role of FAP in renal fibrosis, where FAPI-PET/CT demonstrates superior predictive value for treatment response compared to FDG-PET/CT [30]. However, the functional roles of FAP extend beyond diagnostic applications. FAP overexpression in activated tubular epithelial cells and fibroblasts promotes myofibroblast activation and collagen deposition through extracellular matrix degradation and activation of pro-fibrotic pathways, such as TGF-β and FGF [19, 31, 32], although its precise mechanistic contributions remain incompletely defined. Additionally, FAP modulates immune cell infiltration and retention at inflammatory sites, such as synovium and dermis, via cleavage of chemokines and cytokines, thereby amplifying local immune responses [33, 34]. Notably, in tumor microenvironments, FAP⁺ fibroblasts suppress CD8⁺ T cell function [35], suggesting potential parallel immunosuppressive mechanisms in SLE. Nonetheless, there is no available data supporting the functional role of FAP in SLE.
We have for the first time demonstrated that exosomal FAP serves as a specific SLE biomarker correlated with disease activity. Functionally, dysregulated exosomal FAP may be engaged in immune-inflammatory regulation and tissue remodeling, participating in processes including extracellular matrix degradation, cell migration/adhesion, angiogenesis, cell cycle/proliferation regulation, and fibrinolysis activation. However, the pathogenic mechanism of exosomal FAP in SLE requires further validation.
Exosomal FAP in the Immunometabolic Network of SLE
SLE is characterized by a profound lipid metabolic rewiring that fuels the bioenergetic demands of hyperactive immune cells [13]. Specific fatty acids, such as AA, are crucial modulators of immune response [36]. Our study places exosomal FAP within this immunometabolic context. We identified a pronounced pro-inflammatory fatty acid profile in SLE, marked by elevated saturated fatty acids and AA, decreased DHA and EPA, and significantly increased total ω-6/ω-3 ratio in active SLE. Reduced ω-3 and elevated total ω-6/ω-3 ratio are independent risk factors for cardiovascular disease [37, 38]. Therefore, in SLE, fatty acid metabolic imbalance may represent a crucial link connecting SLE to cardiovascular complications [13]. Fatty acid imbalance is not only a consequence of immune-metabolic disorder in SLE, but also the contributor to chronic inflammation and immune dysregulation.
In the present study, we found that exosomal FAP was positively correlated with the metabolite palmitoylethanolamide (PEA), an endocannabinoid-like mediator with anti-inflammatory and neuroprotective properties [39], in both active and inactive SLE, suggesting a potential compensatory mechanism. The heightened inflammatory state in SLE can induce PEA production [40], which may concurrently elevate FAP⁺ exosome levels and thus orchestrate the anti-inflammatory response and tissue repair. Conversely, the dynamic relationship between FAP and AA reveals a more complex interplay. The shift from a positive correlation in inactive SLE to a strong negative correlation in active SLE may reflect a critical transition in disease pathogenesis. AA itself serves as both a “precursor” and “fuel” for inflammatory signaling pathways [41]. Upon cellular stimulation like inflammation, AA is released from membrane phospholipids by enzymes such as phospholipase A2 and is rapidly converted into a series of potent inflammatory mediators, including prostaglandins, leukotrienes, and thromboxanes [42–44]. We hypothesize that during active SLE, the heightened immune-inflammatory state promotes AA release and its conversion into pro-inflammatory mediators like PGE2 and LTB4. Concurrently, cellular dysfunction may disrupt normal metabolic processes, while simultaneously impairing the production and release of FAP+ exosomes. This reduction in FAP⁺ exosomes may subsequently temper excessive tissue remodeling, potentially limiting long-term fibrotic damage. Thus, FAP may function as an “amplifier” within a metabolic cycle of hyper-synthesis and oxidative damage, potentially forming a positive feedback loop with pro-inflammatory lipids like AA to enhance FAO for energy supply, while suppressing the generation of anti-inflammatory repair factors such as PEA, thereby impeding natural inflammation resolution.
This study further identifies pronounced alterations in fatty acid ratios (AA/DHA, total ω-6/ω-3, EPA/AA) during active SLE. Exosomal FAP levels correlated positively with pro-inflammatory lipids (total ω-6 PUFAs, AA, myristic acid) and negatively with anti-inflammatory mediators (total ω-3, DHA, EPA, alpha-linolenic acid), and were positively associated with AA/DHA and ω-6/ω-3 ratios. Consequently, these ratios, combined with exosomal FAP, show promise as objective, quantifiable blood biomarkers for determining SLE disease activity. In summary, exosomal FAP represents a potential driver of lipid metabolic dysregulation, participates in lipid metabolic reprogramming in SLE, and constitutes a potential therapeutic target.
The combined detection of exosomal FAP and fatty acid metabolic profiles holds significant clinical potential. As diagnostic marker, exosomal FAP combined with fatty acid disturbances constitutes a disease-specific signature complementary to conventional antibodies. For disease activity assessment, dynamic monitoring of this metabolic axis provides a sensitive reflection of pro-inflammatory/anti-inflammatory balance, offering metabolic insights for precise evaluation, relapse prediction, and treatment guidance. Furthermore, our findings suggest dietary modulation of fatty acid intake as a complementary therapeutic strategy, increasing omega-3 consumption (such as EPA/DHA-rich foods) while reducing excessive ω-6 intake to improve the ω-6/ω-3 ratio. Such nutritional interventions represent safe, cost-effective adjuncts to conventional immunosuppressive therapy, potentially improving disease control and reducing relapse rates.
Research Limitations
This study has several limitations. First, the sample size was relatively limited. Future expanded cohorts will help verify the generalizability of our findings across different SLE populations, including patients combined with cardiovascular disorders. Second, this study profiled the free fatty acids in plasma rather than the specific lipid composition within the exosomal lumen. As crucial mediators of intercellular communication, the intraluminal lipid microenvironment of exosomes may hold unique pathophysiological significance. Future work involving the direct isolation and analysis of exosomal fatty acids will provide a more precise understanding of their specific role in SLE pathogenesis. Last but not the least, plasma exosomes in SLE may be derived from the activated fibroblasts, epithelial cells, or specific immune cells. Identifying the parent cells is crucial for understanding the specific pathophysiological role of exosomal FAP in SLE pathogenesis.
Conclusion and outlook
In summary, this study systematically delineates the characteristic alterations in the plasma exosomal proteome and lipidome of SLE patients and, for the first time, establishes a link between exosomal FAP and lipid metabolic reprogramming. We propose that the exosomal FAP-lipid metabolism axis represents a core pathway driving immune inflammation, tissue injury, and cardiovascular complications in SLE. The combined detection of exosomal FAP and characteristic fatty acid profiles, such as the AA/EPA ratio, could provide a novel dimension for SLE diagnosis beyond conventional serological testing. Based on the discovery of lipid metabolic imbalance, the nutritional intervention represents a promising adjunctive strategy that may improve disease control, reduce relapse rates, and mitigate cardiovascular risk, combined with conventional immunosuppressants.
Supplementary Information
Acknowledgements
Not applicable.
Authors' contributions
Donghua Xu, Haibo Li: conception and design, supervision and interpretation, manuscript writing and revising. Jin Zhang, Meiyan Chen, Chunjuan Yang, Mengyao Zhang, Jie Zang: collection and assembly of data, data analysis, collection of study materials, manuscript writing and revising; Wenchang Sun, Hui Wang, Mengyao Zhang, Jiamei Sun: data analysis, collection of study materials, manuscript writing. All the authors have read and approved the final manuscript.
Funding
This study is supported by funds from National Natural Science Foundation of China (82171790), Natural Science Foundation, Shandong Province (ZR2024MH079), and Medical and Health Science and Technology Development Plan, Shandong Province, China (202403110363), and the Graduate Student Research Grant from Shandong Second Medical University (2024YJSCX025), and Science and Technology Innovation Leading Team of Shandong Provincial Health Commission (2025).
Data availability
The data that support the findings of this study are available from the corresponding authors upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Medical Ethics Committee of Weifang People’s Hospital, Shandong Second Medical University. (Approval No. 2021SDL299).
Consent for publication
All the authors have read and approved the final manuscript.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jin Zhang, Meiyan Chen, Chunjuan Yang and Jie Zang contributed equally to this work.
Contributor Information
Haibo Li, Email: zxsys2610@163.com.
Donghua Xu, Email: xudh@sdsmu.edu.cn.
References
- 1.Kiriakidou M, Ching CL. Systemic Lupus Erythematosus, Annals of Internal Medicine. 2020 Jun. 2020;2(11):ITC81–96. 10.7326/aitc202006020. [DOI] [PubMed] [Google Scholar]
- 2.Parra Sánchez AR, Voskuyl AE, van Vollenhoven RF. Treat-to-target in systemic lupus erythematosus: advancing towards its implementation. Nat Reviews Rheumatol 2022 Mar. 18(3): 146–57.10.1038/s41584-021-00739-3 [DOI] [PubMed]
- 3.Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics, Signal Transduction and Targeted Therapy. 2025 Mar 17. 10(1). 10.1038/s41392-025-02168-0 [DOI] [PMC free article] [PubMed]
- 4.Yu H, Nagafuchi Y, Fujio K. Clinical and Immunological Biomarkers for Systemic Lupus Erythematosus, Biomolecules. 2021 Jun 22. 11(7). 10.3390/biom11070928 [DOI] [PMC free article] [PubMed]
- 5.Murimi-Worstell IB, Lin DH, Kan H, Tierce J, Wang X, Nab H, Desta B, Alexander GC, Hammond ER. Healthcare Utilization and Costs of Systemic Lupus Erythematosus by Disease Severity in the United States. J Rheumatol 2021 Mar. 48(3): 385–93.10.3899/jrheum.191187 [DOI] [PubMed]
- 6.Doyle L, Wang M. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis, Cells. 2019 Jul 15. 8(7). 10.3390/cells8070727 [DOI] [PMC free article] [PubMed]
- 7.Cunha e, Rocha K, Ying W, Olefsky JM. Exosome-Mediated Impact on Systemic Metabolism. Annu Rev Physiol. 2024 Feb;12(1):225–53. 10.1146/annurev-physiol-042222-024535. [DOI] [PubMed]
- 8.Yue B, Yang H, Wang J, Ru W, Wu J, Huang Y, Lan X, Lei C, Chen H. Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Prolif 2020 Jul 53(7).10.1111/cpr.12857 [DOI] [PMC free article] [PubMed]
- 9.Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K. Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases. Front Immunol. 2021;12. 10.3389/fimmu.2021.749192. [DOI] [PMC free article] [PubMed]
- 10.Wang Y, Xiang Q, Wu Y, Zhang X, Huang Z, Hou Y, Wang Y, Yang J, Wan W, Zou H. Yang. Mesenchymal Stem Cell-Derived Exosomes Inhibit Stim1–Orai1 Signaling and Calcium Overload-Induced Mitochondrial Damage of Follicular Helper T Cells in Lupus. Biomaterials Res. 2025 Sep;22:29. 10.34133/bmr.0255. [DOI] [PMC free article] [PubMed]
- 11.Zhang X, Xu Y, Ma L, Yu K, Niu Y, Xu X, Shi Y, Guo S, Xue X, Wang Y, Qiu S, Cui J, Wang H, Tian X, Miao Y, Meng F, Qiao Y, Yu Y, Wang J. Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma. Cancer Commun. 2022 Feb;20(42):287–313. 10.1002/cac2.12275. [DOI] [PMC free article] [PubMed]
- 12.Zhang Y, Yi D, Hong Q, Liu C, Chi K, Liu J, Li X, Ye Y, Zhu Y, Peng N. Platelet-rich plasma-derived exosomes enhance mesenchymal stem cell paracrine function and nerve regeneration potential, Biochemical and Biophysical Research Communications. 2024 Jan 8. 699 10.1016/j.bbrc.2024.149496 [DOI] [PubMed]
- 13.Sharabi A, Tsokos GC. T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat Reviews Rheumatol 2020 Jan 16. 16(2): 100–12.10.1038/s41584-019-0356-x [DOI] [PubMed]
- 14.Robinson GA, Knight A, Tucker LB, Belot A, Isenberg DA, Ciurtin C. Insights into the pathogenesis of childhood-onset SLE in the past decade. Nat Rev Rheumatol. 2025 Nov;19. 10.1038/s41584-025-01321-x. [DOI] [PubMed]
- 15.Dawi J, Affa S, Misakyan Y, Fardeheb S, Kades S, Kiriaki A, Mohan AS, Norris B, Yoon S, Venketaraman V. Exploring cardiovascular implications in systemic lupus erythematosus: A holistic analysis of complications, diagnostic criteria, and therapeutic modalities, encompassing pharmacological and adjuvant approaches. Biomol Concepts. 2024 Jan;1(1). 10.1515/bmc-2022-0051. [DOI] [PMC free article] [PubMed]
- 16.Bartoloni E, Cacciapaglia F, Erre GL, Gremese E, Manfredi A, Piga M, Sakellariou G, Spinelli FR, Viapiana O, Atzeni F. Immunomodulation for accelerated atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Autoimmun rev. 2025 Feb;1(4). 10.1016/j.autrev.2025.103760. [DOI] [PubMed]
- 17.Matsuura E, Kobayashi K, Tabuchi M, Lopez L. Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis, Progress in Lipid Research. 2006 May 30. 45(6): 466–86 10.1016/j.plipres.2006.05.001. [DOI] [PubMed]
- 18.Ferreira HB, Pereira AM, Melo T, Paiva A, Domingues MR. Lipidomics in autoimmune diseases with main focus on systemic lupus erythematosus. J Pharm Biomedical Anal 2019 Jun 6. 174: 386–95 10.1016/j.jpba.2019.06.005. [DOI] [PubMed]
- 19.Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy. Proteom – Clin Appl. 2014 Mar;24(5–6):454–63. 10.1002/prca.201300095. [DOI] [PubMed]
- 20.Ma J, Huang Y, Chen J, Li Y, Yao R, Li X, Liang Q, Chen X, Peng C, Liu K, Zhai Y, Zhang X, Ma X, Wang X, Huang Q, He F. FAP+ fibroblasts orchestrate tumor microenvironment remodeling in renal cell carcinoma with tumor thrombus. Nat Commun. 2025 Oct;23(1). 10.1038/s41467-025-64447-2. [DOI] [PMC free article] [PubMed]
- 21.Chocarro-Calvo A, Jociles-Ortega M, García-Martinez JM, Louphrasitthiphol P, Carvalho-Marques S, Vivas-García Y, Ramírez-Sánchez A, Chauhan J, Fiuza MC, Duran M, Sánchez-Danés A, Goding CR. García-Jiménez. Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression. Genes Dev. 2025 Apr;1(7–8):463–89. 10.1101/gad.351985.124. [DOI] [PMC free article] [PubMed]
- 22.Ma H, Wang J, Zhao X, Wu T, Huang Z, Chen D, Liu Y, Ouyang G. Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation, Cell Reports. 2020 Jan 21. 30(3): 793–e8066. 10.1016/j.celrep.2019.12.075 [DOI] [PubMed]
- 23.Wang Y, Plastina P, Vincken J-P, Jansen R, Balvers M, ten Klooster JP, Gruppen H, Witkamp R, Meijerink J. N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2, ACS Chemical Neuroscience. 2016 Dec 6. 8(3): 548–57. 10.1021/acschemneuro.6b00298 [DOI] [PubMed]
- 24.Chitre NM, Wood BJ, Ray A, Moniri NH, Murnane KS. Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson’s disease via mechanisms associated with increased protein kinase activity in the striatum, Neuropharmacology. 2020 Jan 27. 167 10.1016/j.neuropharm.2020.107976 [DOI] [PMC free article] [PubMed]
- 25.Gao J, Song X, Chen J, Liu X, Liu H. Exosomes from systemic lupus erythematosus (SLE) patients facilitate the production of inflammatory cytokines in dendritic cells (DCs) by regulating the mTOR signaling. Hum Immunol. 2025 Aug;6(5):86. 10.1016/j.humimm.2025.111563. [DOI] [PubMed]
- 26.Wang Z-y, Liu W-j, Jin Q-y, Zhang X-s, Chu X-j, Khan A, Zhan S-b, Shen H, Yang P. Machine Learning-Based Identification of Novel Exosome-Derived Metabolic Biomarkers for the Diagnosis of Systemic Lupus Erythematosus and Differentiation of Renal Involvement. Curr Med Sci. 2025 Feb;28(2):231–43. 10.1007/s11596-025-00023-5. [DOI] [PubMed]
- 27.Zhang N, Dong N, Xie A, Liu W, Khan A, Rui Y, Yang P. Urinary extracellular vesicle metabolomic profiling reveals a distinct molecular signature for the non-invasive diagnosis of lupus nephritis. Front Immunol 2026 Feb 17. 17doi:10.3389/fimmu.2026.1741455 [DOI] [PMC free article] [PubMed]
- 28.Lu L, Gao Y, Huang D, Liu H, Yin D, Li M, Zheng J, Wang S, Wu W, Zhao L, Bi D, Zhang Y, Song F, Xie R, Wang J, Qin H, Wei Q. Targeting integrin α5 in fibroblasts potentiates colorectal cancer response to PD-L1 blockade by affecting extracellular-matrix deposition. J Immunother Cancer. 2023 Dec;1(12). 10.1136/jitc-2023-007447. [DOI] [PMC free article] [PubMed]
- 29.Sun Y, Ma M, Cao D, Zheng A, Zhang Y, Su Y, Wang J, Xu Y, Zhou M, Tang Y, Liu Y, Ma T, Fan A, Zhang X, Zhu Q, Qin J, Mo C, Xu Y, Zhang L, Xu D. Yue. Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP. Circul Res. 2023 Feb;9(5):586–600. 10.1161/circresaha.122.320781. [DOI] [PubMed]
- 30.Zhao M, Zhou C, Fang H, Cao Y, Hacker M, Li X, Guo M, Yi X, Zhang X. [18F]F-FAPI PET/CT outperforms [18F]F-FDG PET/CT in predicting treatment response in lupus nephritis, European Journal of Nuclear Medicine and Molecular Imaging. 2025 Aug 20. 10.1007/s00259-025-07523-5 [DOI] [PubMed]
- 31.Yu S, Yang Z, Ding Z, Jia Y, Wan L, Li L, Lv J, Pan H, Qian J, Wei X, Yang Y, Zan Y, Teng J, Li B, Yang C, Xu J, Xue L, Shi H. Zhang. 68Ga-FAPI-04 PET/CT Imaging for Assessing Renal Tubulointerstitial Fibrosis in Lupus Nephritis. J Nucl Med. 2025 Mar;3(3):418–24. 10.2967/jnumed.124.268643. [DOI] [PubMed]
- 32.Alemany M, Coppage AL, Heard KR, DiMare MT, Liu Y, Wu W, Lai JH. Bachovchin. Human FGF-21 Is a Substrate of Fibroblast Activation Protein. PLoS ONE. 2016 Mar;10(3). 10.1371/journal.pone.0151269. [DOI] [PMC free article] [PubMed]
- 33.Yin C, Fu L, Guo S, Liang Y, Shu T, Shao W, Xia H, Xia T, Wang M. Senescent Fibroblasts Drive FAP/OLN Imbalance Through mTOR Signaling to Exacerbate Inflammation and Bone Resorption in Periodontitis. Adv Sci. 2024 Dec;24(7). 10.1002/advs.202409398. [DOI] [PMC free article] [PubMed]
- 34.Rauber S, Mohammadian H, Schmidkonz C, Atzinger A, Soare A, Treutlein C, Kemble S, Mahony CB, Geisthoff M, Angeli MR, Raimondo MG, Xu C, Yang K-T, Lu L, Labinsky H, Saad MSA, Gwellem CA, Chang J, Huang K, Kampylafka E, Knitza J, Bilyy R, Distler JHW, Hanlon MM, Fearon U, Veale DJ, Roemer FW, Bäuerle T, Maric HM, Maschauer S, Ekici AB, Buckley CD, Croft AP, Kuwert T, Prante O, Cañete JD, Schett G. Ramming. CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis. Nat Immunol. 2024 Feb;23(4):682–92. 10.1038/s41590-024-01774-4. [DOI] [PubMed]
- 35.Wei R, Song J, Liu C, Zhao Z, Liu X, Yamamoto M, Tsukamoto T, Nomura S, Liu F, Wang Y, Liu X. FAP upregulates PD-L1 expression in cancer-associated fibroblasts to exacerbate T cells dysfunction and suppress anti-tumor immunity. Cancer Lett. 2025 Jan;18:612doi. 10.1016/j.canlet.2025.217475. [DOI] [PubMed]
- 36.Huang N, Wang M, Peng J, Wei H. Role of arachidonic acid-derived eicosanoids in intestinal innate immunity. Crit Reviews Food Sci Nutr 2020 Jul 14. 61(14): 2399–410 10.1080/10408398.2020.1777932. [DOI] [PubMed]
- 37.Redruello-Requejo M, Samaniego-Vaesken MdL, Puga AM, Montero-Bravo A, Ruperto M, Rodríguez-Alonso P, Partearroyo T, Varela-Moreiras G. Omega-3 and Omega-6 Polyunsaturated Fatty Acid Intakes, Determinants and Dietary Sources in the Spanish Population: Findings from the ANIBES Study, Nutrients. 2023 Jan 21. 15(3).10.3390/nu15030562 [DOI] [PMC free article] [PubMed]
- 38.Ambler WG, Kaplan MJ. Vascular damage in systemic lupus erythematosus. Nat Rev Nephrol. 2024 Jan;3(4):251–65. 10.1038/s41581-023-00797-8. [DOI] [PMC free article] [PubMed]
- 39.Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci. 2021 May;18(10):22. 10.3390/ijms22105305. [DOI] [PMC free article] [PubMed]
- 40.Xiao D, Kong T, Wang T, Huang H, Qin W, Zhao B, Chen H, Wu X, Wang K, Zheng J. Serum protein profiles in lupus nephritis associated with initial-onset systemic lupus erythematosus: Characterization through PEA immunoassay and preliminary development of predictive model, Cytokine. 2026 Jan. 197. 10.1016/j.cyto.2025.157065 [DOI] [PubMed]
- 41.He J, Ma C, Tang D, Zhong S, Yuan X, Zheng F, Zeng Z, Chen Y, Liu D, Hong X, Dai W, Yin L, Dai Y. Absolute quantification and characterization of oxylipins in lupus nephritis and systemic lupus erythematosus. Front Immunol. 2022 Oct;6:13. 10.3389/fimmu.2022.964901. [DOI] [PMC free article] [PubMed]
- 42.Santiago Valtierra FX, Urriola-Muñoz P, Godoy-Sepúlveda R, Moreno RD, Reyes JG, Vallés AS, Oresti GM. Nonylphenol releases arachidonic acid in rat Sertoli cells via activation of PKA and PLA2, Reproduction. 2024 Jun 13. 168(1). 10.1530/rep-23-0292 [DOI] [PubMed]
- 43.Ashton AW, Zhang Y, Cazzolli R, Honn KV. The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection, Molecules. 2022 Sep 22. 27(19).10.3390/molecules27196234 [DOI] [PMC free article] [PubMed]
- 44.Huang Y-H, Sharifpanah F, Becker S, Wartenberg M, Sauer H. Impact of Arachidonic Acid and the Leukotriene Signaling Pathway on Vasculogenesis of Mouse Embryonic Stem Cells. Cells Tissues Organs. 2016 May;21(5):319–32. 10.1159/000445680. [DOI] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding authors upon reasonable request.