Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling

  • Nat Commun. 2026 Mar 24;17(1):5036. doi: 10.1038/s41467-026-70410-6.
Shiju Ye  #  1  2  3  4 ,  Yanbo Zhao  #  2  3 ,  Hanxiao Tu  #  5 ,  Xue Han  1 ,  Tong Liu  6 ,  Yingchao Gong  2  3 ,  Jiangting Lu  2  3 ,  Tingting Jin  2  3 ,  Wu Luo  1  4 ,  Xuefeng Qu  1 ,  Dongwu Lai  2  3 ,  Guosheng Fu  7  8  9 ,  Guang Liang  10  11
Affiliations
  • 1. International Laboratory of Cardiovascular Diseases, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2. Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 4. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5. Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6. School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 7. Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
  • 8. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang, China. [email protected].
  • 9. School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 10. International Laboratory of Cardiovascular Diseases, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 11. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41876530 DOI: 10.1038/s41467-026-70410-6
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.

Products