{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:59:38Z","timestamp":1790283578759,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA1100500"],"award-info":[{"award-number":["2021YFA1100500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2507100"],"award-info":[{"award-number":["2023YFC2507100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Nova Program","doi-asserted-by":"publisher","award":["UHB11839"],"award-info":[{"award-number":["UHB11839"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Autoimmune diseases, such as systemic lupus erythematosus (SLE), are associated with pulmonary arterial hypertension (PAH), a condition that can lead to heart failure. However, whether T cells also contribute to the occurrence of PAH in SLE has not been clarified. The objective of this study was to elucidate the role of Activin A and activated receptor signaling in SLE\u2010PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mass Cytometry (CyTOF) analysis was performed to identify the major affected immune cell population in patients with SLE\u2010PAH. Serum Activin A and interleukin\u201017 (IL\u201017) levels in patients with SLE\u2010PAH, patients with SLE, and healthy donors were determined by enzyme\u2010linked immunosorbent assay. Cocultures of Th17 cells with pulmonary microvascular endothelial cells (PMECs) and relevant rodent models were used to identify the converged target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The reduced CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell number was detected in patients with SLE\u2010PAH after treatment with immunosuppressant and vasodilator. Increased Th17 cells population and higher serum Activin A and IL\u201017 levels were found in patients with SLE\u2010PAH compared to patients with SLE only or donors. Activin A signals via activin receptor\u2013like kinase 4 (ALK4) in both Th17 cells and PMECs. Overexpressing ALK4 in Th17 cells increased IL\u20106 and endothelial\u2013mesenchymal transition (EndoMT) marker levels in cocultured PMECs. We found severe SLE\u2013pulmonary hypertension (PH) in mice by overexpressing ALK4, and alleviated hemodynamic changes in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells depletion mice. ALK4 inhibitor vactosertib (TEW\u20107197) effectively treated SLE\u2010PH mice by repressing connective tissue growth factor (\n                      <jats:italic>CTGF<\/jats:italic>\n                      ) transcription, which was induced by ALK4 activated pSmad2 and pSTAT3.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that Activin A activates ALK4 in Th17 cells, thereby inducing IL\u201017 secretion. Concurrently, activated ALK4 induces EndoMT in human PMECs (hPMECs) via CTGF up\u2010regulation. It suggests that ALK4 is a promising therapeutic target for SLE\u2010PAH.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43235-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.43235","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T04:20:00Z","timestamp":1747801200000},"page":"1533-1547","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Activin A\u2013Activated\n                    <scp>ALK4<\/scp>\n                    Induces Pathogenic Th17\u2010Involved Endothelial\u2013Mesenchymal Transition in Systemic Lupus Erythematosus\u2013Associated Pulmonary Arterial Hypertension"],"prefix":"10.1002","volume":"77","author":[{"given":"Shuliang","family":"Jing","sequence":"first","affiliation":[{"name":"Department of Physiology and Department of Cardiology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-539X","authenticated-orcid":false,"given":"Junyan","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Peking Union Medical College Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Physiology and Department of Cardiology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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