{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T19:53:00Z","timestamp":1785268380681,"version":"3.55.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Systemic sclerosis (Scleroderma; SSc) is associated with high morbidity and mortality, particularly in patients with pulmonary arterial hypertension (SSc-PAH) and pulmonary fibrosis (SSc-PF). Effective risk stratification and treatment of SSc remains a significant challenge. This proof-of-concept study aimed to identify potential biomarkers capable of distinguishing between three SSc patient groups, defined by no pulmonary involvement (SSc-NLD; n=30), SSc-PAH (n=30), SSc-PF (n=30) compared to healthy controls (HC; n=30).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The study employed Olink-based proteomics using the Cardiovascular II and Immuno-oncology panels, and untargeted metabolomic profiling using Ultra-high Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS\/MS), to discover distinct molecular signatures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Proteomics analysis revealed significantly elevated levels of MCP-1, MCP-3, and MCP-4 in SSc-PF compared to all other groups. However, no robust discriminatory cytokines were identified for SSc-PAH or SSc-NLD. Validation of systemic MCP-1 and IL-6 by ELISA supported the proteomics findings. IL-33 levels were found to be reduced in the SSc-PAH group. Increased levels of pro-inflammatory sIL-6R were also identified in SSc-PAH and SSc-PF, indicating shared inflammatory pathways. Protein-protein interaction analyses demonstrated greater network complexity in SSc-PF, with pathway analysis suggesting overlapping biological mechanisms across pulmonary groups. Metabolomics analysis uncovered a unique panel of metabolites altered exclusively in SSc-PAH, including quinolinate, dimethylarginines, hydroxyasparagine and orotidine. In contrast, no metabolites were uniquely discriminatory for SSc-PF or SSc-NLD. Metabolite-metabolite interaction networks revealed nicotinate and nicotinamide metabolism as the more significantly enriched metabolic pathways in SSc-PAH. Correlation analyses identified distinct protein-metabolite profiles across groups. Of note is the loss of IL-33-related metabolic associations specific to SSc-PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study identified a candidate biomarker panel comprising three cytokines and ten metabolites capable of differentiating between SSc-PAH, SSc-PF, SSc-NLD, and HC. Biomarkers of SSc-PAH were linked to nicotinate and nicotinamide, as well as tryptophan metabolism, whereas those of SSc-PF reflected immune cell infiltration and fibrosis. These findings highlight the potential biomarker panels for diagnosis and targeted therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1755076","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T06:32:04Z","timestamp":1770013924000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Systemic sclerosis-associated pulmonary arterial hypertension and pulmonary fibrosis: exploring biomarker discriminators with advanced omics in a Caucasian cohort"],"prefix":"10.3389","volume":"17","author":[{"given":"Nada","family":"Mohamed-Ali","sequence":"first","affiliation":[{"name":"Centre of Metabolism and Inflammation, Department of Inflammation and Rare Diseases, Division of Medicine, University College London","place":["London, United 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