{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:51:19Z","timestamp":1782449479919,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pulmonary hypertension (PH) is a severe, progressive pulmonary vascular disease characterized by a sustained elevation of pulmonary vascular resistance,\n                      <jats:italic>in situ<\/jats:italic>\n                      thrombosis, and progressive vascular remodeling, with limited therapeutic options. In the present study, we aimed to determine whether TRAF6 (tumor necrosis factor receptor-associated factor 6) exacerbates the progression of PH and to elucidate the underlying molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study examined the protein expression and phosphorylation levels of TRAF6 and signal transducer and transcription activator 3 (STAT3), as well as key biological indicators related to cell proliferation, apoptosis, and migration. By genetic knockdown of TRAF6, we investigated its regulatory role and underlying mechanisms in pulmonary vascular remodeling in both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models of PH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We employed the monocrotaline (MCT)-induced rat PH model, in which overt pulmonary vascular wall thickening and right ventricular (RV) functional impairment progressively develop. We demonstrate that lung-specific knockdown of TRAF6 markedly attenuates established pulmonary vascular remodeling, improves right ventricular function, and corrects aberrant pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. The molecular interaction between TRAF6 and STAT3 was experimentally confirmed, showing that TRAF6 controls the amount of STAT3 protein and its phosphorylation status by adding ubiquitin to it.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study confirmed that TRAF6 plays a key pathogenic role in pulmonary hypertension by promoting STAT3 ubiquitination and sustained activation, thereby accelerating pulmonary vascular remodeling and disease progression. These findings provide a novel mechanistic insight into the progression of PH and highlight TRAF6 as a promising therapeutic target in PH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1850163","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:38:39Z","timestamp":1782448719000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TRAF6 promotes pulmonary hypertension by enhancing K63-linked ubiquitination and activation of STAT3"],"prefix":"10.3389","volume":"17","author":[{"given":"Meijing","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengran","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengqiu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingbing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e70134","DOI":"10.1002\/mco2.70134","article-title":"Pulmonary hypertension: molecular mechanisms and clinical studies","volume":"6","author":"Adu-Amankwaah","year":"2025","journal-title":"MedComm"},{"key":"B2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3390\/ijms22179105","article-title":"Combination therapy with STAT3 inhibitor enhances SERCA2a-Induced BMPR2 expression and inhibits pulmonary arterial hypertension","volume":"24","author":"Bisserier","year":"2021","journal-title":"Int. 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