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Protein kinases act as key regulators in cellular actions relevant to cardiac pathophysiology. This study identified a protein kinase, Wee1 G2 checkpoint kinase (Wee1), being activated and involved in this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RNA-seq-based kinase enrichment analysis was used to identify the involved kinase pathways. Cardiomyocyte-specific Wee1-deficiency mice with chronic angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodelling. RNA-seq and co-immunoprecipitation were used to explore the mechanism and substrate of Wee1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Kinase enrichment analysis and experimental evidence revealed that Wee1 phosphorylation at Ser642, but not increased expression, was observed in hypertrophic cardiac tissues from both mice and human patients. Knockdown, pharmacological inhibition, or mutational inactivation of Wee1 significantly alleviated Ang II-induced cardiomyocyte injuries. RNA-seq analysis showed that phosphoinositide 3-kinases\/protein kinase B (AKT) pathway mediated the function of Wee1 in cardiomyocytes. Mechanistically, the phosphorylated Wee1 directly binds to the PHD domain of AKT to phosphorylate AKT inducing AKT\/phosphoinositide 3-kinases\u2013nuclear factor \u03baB signalling pathway activation and subsequent inflammation and hypertrophy in cardiomyocytes. Cardiomyocyte-specific Wee1 deficiency was found to protect against cardiac inflammation, remodelling, and dysfunction in mice subjected to transverse aortic constriction or Ang II infusion. Pharmacological Wee1 inhibition also attenuated Ang II-induced cardiac remodelling in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Cardiomyocyte Wee1 activation drives inflammation and hypertrophy by directly phosphorylating AKT and activating AKT\u2013nuclear factor \u03baB pathway. This study identifies Wee1 as a new upstream kinase of AKT and a potential therapeutic target for hypertensive heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf349","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T07:46:10Z","timestamp":1746690370000},"page":"1702-1717","source":"Crossref","is-referenced-by-count":12,"title":["Checkpoint kinase Wee1 activation drives inflammation and hypertrophy through the protein kinase B\/phosphoinositide 3-kinases\u2013nuclear factor \u03baB pathway in cardiomyocytes"],"prefix":"10.1093","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7340-1568","authenticated-orcid":false,"given":"Mengyang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital, Hangzhou Medical College , No. 158 Shangtang Road, Hangzhou, Zhejiang 310014 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