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Matrix stiffening early in the disease promotes remodeling in pulmonary artery smooth muscle cells (PASMCs), contributing to PAH pathogenesis. Our research identified YAP and TAZ as key drivers of the mechanobiological feedback loop in PASMCs, suggesting targeting them could mitigate remodeling. However, YAP\/TAZ are ubiquitously expressed and carry out diverse functions, necessitating a cell\u2010specific approach. Our previous work demonstrated that targeting non\u2010canonical IKB kinase TBK1 reduced YAP\/TAZ activation in human lung fibroblasts. Here, we investigate non\u2010canonical IKB kinases TBK1 and IKK\u03b5 in pulmonary hypertension (PH) and their potential to modulate PASMC pathogenic remodeling by regulating YAP\/TAZ. We show that TBK1 and IKK\u03b5 are activated in PASMCs in a rat PH model. Inflammatory cytokines, elevated in PAH, activate these kinases in human PASMCs. Inhibiting TBK1\/IKK\u03b5 expression\/activity significantly reduces PAH\u2010associated PASMC remodeling, with longer\u2010lasting effects on YAP\/TAZ than treprostinil, an approved PAH therapy. These results show that non\u2010canonical IKB kinases regulate YAP\/TAZ in PASMCs and may offer a novel approach for reducing vascular remodeling in PAH.<\/jats:p>","DOI":"10.14814\/phy2.15999","type":"journal-article","created":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T03:38:31Z","timestamp":1712979511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Non\u2010canonical <scp>IKB<\/scp> kinases regulate <scp>YAP<\/scp>\/<scp>TAZ<\/scp> and pathological vascular remodeling behaviors in pulmonary artery smooth muscle cells"],"prefix":"10.14814","volume":"12","author":[{"given":"Aja","family":"Aravamudhan","sequence":"first","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Dieffenbach","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and 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