{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T09:52:52Z","timestamp":1781603572627,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":166,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32400808"],"award-info":[{"award-number":["32400808"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and progressive fibrosis. Although microvascular injury is an inciting event and pericytes are recognized as a major source of myofibroblasts, the precise phenotypic heterogeneity of pericytes in the SSc microenvironment and the genetic mechanisms driving their pathological transition remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study systematically explored the cellular and genetic basis of pericyte dysfunction by integrating single\u2010cell RNA sequencing (scRNA\u2010seq) data from SSc patients with genome\u2010wide association study (GWAS) data using bidirectional Mendelian randomization (MR) analysis. Pseudotime trajectory analysis was used to reconstruct developmental lineages, while cell\u2013cell communication and metabolic pathway analyses were conducted to uncover underlying mechanisms. Multiomics validation was performed using external bulk RNA\u2010seq datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single\u2010cell analysis revealed significant heterogeneity in pericyte subpopulations, specifically identifying a marked expansion of progenitor\u2010like pericytes, which were positioned at the root of the differentiation trajectory toward fibrotic phenotypes. Bidirectional MR analysis identified\n                      <jats:italic>RAC1<\/jats:italic>\n                      as a significant causal risk factor for SSc (OR\u2009=\u20092.0756,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009 = 0.0046). Mechanistically,\n                      <jats:italic>RAC1<\/jats:italic>\n                      \u2010positive pericytes exhibited enhanced proinflammatory crosstalk with macrophages via the MIF\u2010(CD74\u2009+\u2009CD44) signaling axis. Furthermore, these activated pericytes displayed distinct metabolic reprogramming, characterized by the upregulation of riboflavin and thiamine metabolism to support their bioenergetic demands. Transcriptomic validation further confirmed the aberrant overexpression of\n                      <jats:italic>RAC1<\/jats:italic>\n                      in SSc tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study establishes a mechanistic link between\n                      <jats:italic>RAC1<\/jats:italic>\n                      \u2010mediated activation of progenitor\u2010like pericytes and SSc pathogenesis.\n                      <jats:italic>RAC1<\/jats:italic>\n                      acts as a causal driver promoting pathological pericyte transition and orchestrates a proinflammatory microenvironment through metabolic reprogramming and immune recruitment, offering a novel therapeutic target for SSc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/6166654","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T09:02:55Z","timestamp":1781600575000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Single\u2010Cell Transcriptomics and Mendelian Randomization to Identify RAC1 as a Causal Metabolic Driver of Pericyte Dysfunction in Systemic 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