{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:10:45Z","timestamp":1790856645384,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,3,13]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Atherosclerotic vascular diseases remain the leading cause of death despite the use of lipid-lowering drugs. The development of more efficacious therapies targeting endothelial inflammation and endothelial-to-mesenchymal transition (EndMT) is an essential endeavor, aiming for better treatment outcomes. The increased mutation frequency of the\n                      <jats:italic toggle=\"yes\">TBK1<\/jats:italic>\n                      (TANK-binding kinase 1) gene has been observed in patients with coronary heart disease. However, the precise function of TBK1 in endothelial dysfunction, inflammation, and atherogenesis is yet to be elucidated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      The results of liquid chromatography-mass spectrometry, immunostaining, RNA sequencing, and Western blot in mouse and human arteries with atherosclerotic plaques identified TBK1 as one of the key mediators of EndMT and atherogenesis. Its role was then investigated in endothelium-specific TBK1 knockdown\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice. To gain mechanistic insights, TurboID-based liquid chromatography-mass spectrometry and co-immunoprecipitation techniques were used. The potential therapeutic efficacy of a putative TBK1 inhibitor, GSK8612 (TANK-binding kinase 1 [TBK1] inhibitor), was evaluated in\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice and human endothelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      An increased expression of TBK1 was observed by liquid chromatography-mass spectrometry analysis in the aortas of\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice on a Western diet in comparison with those of normal diet\u2013fed mice. Increased endothelial TBK1 phosphorylation at Ser172 (serine 172; reflecting the elevated TBK1 activation) was detected in human and mouse atherosclerotic arteries. Furthermore, atherogenic factors, TNF-\u03b1 (tumor necrosis factor-alpha) and IL-1\u03b2 (interlukin-1\u03b2), induced a rapid and sustained phosphorylation of TBK1 at S172 in human endothelial cells. RNA sequencing analysis revealed that TBK1 activation promoted EndMT, a pivotal event during the development of atherosclerosis. TBK1 activation increased the expression of EndMT markers in endothelial cells. Of greater significance, endothelium-specific TBK1 knockdown inhibited the development of atherosclerosis in both male and female\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice. Moreover, TBK1 knockdown reduced EndMT both in vivo and in vitro. Mechanistically, TBK1 activation led to phosphorylation of RAC1 (Ras-related C3 botulinum toxin substrate 1)-PAK1 (p21-activated protein kinase) and subsequent phosphorylation of ERK1\/2 (extracellular signal-regulated protein kinases 1 and 2), thereby initiating EndMT. This is achieved by the TBK1 interaction with a PAK1IP1 (PAK1 interacting protein 1), resulting in a reduced binding of PAK1IP1 to PAK1. Furthermore, chronic administration of a TBK1 inhibitor, GSK8612, suppressed EndMT and the formation of atherosclerotic plaques in\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice without affecting serum lipid levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>The interaction between activated TBK1 and PAK1IP1 inhibits the binding of PAK1IP1 to PAK1, which, in turn, increases the phosphorylation of PAK1 and ERK1\/2 in endothelial cells. This process drives EndMT. Endothelium-specific TBK1 knockdown or GSK8612 treatment inhibits EndMT and plaque formation. Safe TBK1 inhibitors could be developed into effective agents for the treatment of atherosclerotic vascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326815","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T10:00:14Z","timestamp":1770976814000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Endothelial TBK1 Deficiency Inhibits Endothelial-to-Mesenchymal Transition and Atherogenesis Through Suppressing PAK1\/ERK1\/2 Signaling"],"prefix":"10.1161","volume":"138","author":[{"given":"Yujie","family":"Pu","sequence":"first","affiliation":[{"name":"Department of Biomedical Science (Y.P., P.D., L.H., Y.W., Q.C., C.K.C., L.W., Y.H.), City University of Hong Kong, China."},{"name":"City University of Hong Kong Shenzhen Research Institute, China (Y.P.)."},{"name":"Hong Kong Centre for Cerebro-Cardiovascular Health Engineering, China (Y.P., Y.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8540-2753","authenticated-orcid":true,"given":"Peihua","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science (Y.P., P.D., L.H., Y.W., Q.C., C.K.C., L.W., Y.H.), City University of Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science (Y.P., P.D., L.H., Y.W., Q.C., C.K.C., L.W., Y.H.), City University of Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6575-5410","authenticated-orcid":true,"given":"Juan","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences (Y.P., L.H., J.H., J.-Y.L., Y.H.), The Chinese University of Hong 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Pathophysiology, School of Basic Medical Sciences, Shenzhen University Medical School, China (C.-L.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1894-3253","authenticated-orcid":true,"given":"Gang","family":"Fan","sequence":"additional","affiliation":[{"name":"Urology Department, Huazhong University of Science and Technology Union Shenzhen Hospital, The 6th Affiliated Hospital of Shenzhen University Medical School, China (G.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8969-6029","authenticated-orcid":true,"given":"Chak Kwong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science (Y.P., P.D., L.H., Y.W., Q.C., C.K.C., L.W., Y.H.), City University of Hong Kong, 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