Abstract
Hypertensive heart failure highlights an urgent need for effective therapeutic strategies. Protein kinases regulate multiple pathways in cardiac pathophysiology and may provide promising therapeutic targets. Here, we identified a Cyclin-dependent kinase, CDK9, promoting inflammation and cardiac remodeling in terminally differentiated cardiomyocytes. Firstly, kinase enrichment analysis and experimental evidence revealed CDK9 phosphorylation at Thr-186 in both human and mouse hypertrophic heart tissues. CDK9 loss of function via T186A mutation in cardiomyocytes attenuated Ang II-induced heart remodeling and NF-κB-mediated inflammation, whereas CDK9 overactivation by T186E mutation induces. This regulatory function of CDK9 in cardiac remodeling is cell cycle-independent. Further studies demonstrate that the kinase domain of CDK9 directly binds to NF-κB P65 protein, which leads to the CDK9/P65 complex nuclear translocation, P65 phosphorylation, and transcription of inflammatory and hypertrophic genes in cardiomyocytes. This process requires CDK9 Thr-186 phosphorylation and Cyclin T1 presence, but is independent on IKKβ and CDK9-RNAPII pathways. Pharmacological inhibition of CDK9 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Collectively, Ang II-activated CDK9 directly binds to and phosphorylates P65 to drive cardiac inflammation and remodeling. This study identifies CDK9 as a potential target in heart failure therapeutics.
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Data availability
The raw bulk RNA-sequencing data have been deposited in the Sequence Read Archive (SRA) under BioProject accession number PRJNA1012513. The raw data of mass spectrometry Data are available via the PRIDE database under accession code PXD074483, and the raw data of mass spectrometry Data of Quantitative Phosphoproteomics are available via the PRIDE database under accession code PXD074496. Source data are provided with this paper.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (U24A20814 to G.L., 82570395 to S.Y., 82370334 to D.L.), the China National Postdoctoral Program for Innovative Talents (BX20240329 to S.Y.), the Postdoctoral Science Foundation (2025M772361 to S.Y.), and the Zhejiang Provincial Natural Science Foundation of China (LMS26H020006 to S.Y.).
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Guang Liang, Guosheng Fu and Yanbo Zhao contributed to the literature search and study design. Guang Liang and Shiju Ye participated in the drafting of the article. Shiju Ye, Hanxiao Tu, Xue Han, Tong Liu, Yingchao Gong, Jiangting Lu, Tingting Jin and Wu Luo carried out the experiments. Yingchao Gong and Dongwu Lai collected the Clinical samples. Yanbo Zhao, Xuefeng Qu, and Guang Liang revised the manuscript. Shiju Ye, Yanbo Zhao and Hanxiao Tu contributed to data collection and analysis.
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Ye, S., Zhao, Y., Tu, H. et al. Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70410-6
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DOI: https://doi.org/10.1038/s41467-026-70410-6
