{
  "abstract": "Introduction Systemic sclerosis is a progressive autoimmune disease marked by skin and internal organ fibrosis, driven largely by the differentiation of fibroblasts into myofibroblasts and the excessive deposition of extracellular matrix. Despite advances in understanding fibrotic mechanisms, effective therapies remain limited, emphasizing the need for deeper molecular insight.Material and Methods The project used in vitro models of pro-fibrotic (TGFb) stimulation and anti-fibrotic (nintedanib) intervention on primary skin fibroblasts from SSc patients and healthy controls. Unbiased metabolomic and transcriptomic (RNA-seq) profiling allowed comprehensive analysis of baseline and treatment-induced molecular alterations.Results Baseline metabolomic profiling on cultured fibroblasts revealed modest differences between SSc and controls, identifying just two discriminant metabolites: 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid and LysoPE (P-16:0/0:0). In contrast, baseline transcriptomic profiling identified 951 dysregulated genes, with top hits including UBA5, ACAD11, PEG10, KIAA1217, and AOX1, each linked to metabolic, cytoskeletal, and fibrotic processes ( figure 1A). Gene set enrichment highlighted cytoskeletal and extracellular matrix functional dysregulation (figure 1B).TGFb treatment robustly induced a fibrotic response by increasing ACTA2, collagen and fibronectin markers (figure 2A) and a metabolic shift, notably marked by the accumulation of five N-lactoyl–amino acids (figure 2B). The increase in these metabolites, formed by the conjugation of lactate and amino acids, suggest enhanced glycolysis and altered energy metabolism during fibrotic activation. Importantly, nintedanib pretreatment reduced both fibrotic gene expression (figure 2C) and N-lactoyl–amino acid accumulation (figure 2D), with 34% of TGFb-altered genes normalized, underscoring its therapeutic mechanism (figure 2E).Transcriptomic and metabolomic shifts were reflected by dysregulation of several lactate metabolism-related genes, including CNDP2, MCT1, MCT2, and MCT4, confirming a metabolic reprogramming from oxidative phosphorylation to glycolysis as a hallmark of TGFb-induced fibrosis.Conclusions Combined multi-omics profiling shows that SSc skin fibroblasts undergo profound transcriptomic changes and distinct metabolic remodeling under pro-fibrotic conditions, including an increase in N-lactoyl–amino acid production and upregulation of lactate metabolism genes. These molecular hallmarks are partially reversed by nintedanib.Abstract OC.44 Figure 1Abstract OC.44 Figure 2",
  "authors": [
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden"
      ],
      "name": "Amin Ravaei"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden"
      ],
      "name": "Yuan Zhang"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden"
      ],
      "name": "Cecilia Överdahl"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden"
      ],
      "name": "Rille Pullerits"
    },
    {
      "affiliations": [
        "Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland, Zurich, Switzerland"
      ],
      "name": "Oliver Distler"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden"
      ],
      "name": "Cristina Maglio"
    }
  ],
  "title": "OC.44 N-lactoyl–amino acids as metabolic signatures of fibrotic transformation in systemic sclerosis skin: insights from integrated metabolomic and transcriptomic analysis",
  "uid": "5a0fc2a4-bd2b-5fb9-bf1f-a9a854227f9b"
}